Simian adenovirus vectors and methods of use

ABSTRACT

A recombinant vector comprises a simian adenovirus capsid and a heterologous gene under the control of regulatory sequences. A cell line which expresses simian adenovirus gene(s) is also disclosed. Methods of using the vectors and cell lines are provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This is a continuation-in-part of International PatentApplication No. PCT/US02/15239, filed May 13, 2002, which claims thebenefit under 35 USC 119(e) of U.S. patent application Ser. No.60/304,843, filed Jul. 12, 2001 and U.S. patent application Ser. No.60/300,131, filed Jun. 22, 2001, all of which are incorporated byreference.

[0002] This is also a continuation-in-part of International PatentApplication No. PCT/US02/33645, filed Nov. 20, 2002, which claims thebenefit under 35 USC 119(e) of U.S. patent application Ser. No.60/366,798, filed Mar. 22, 2002, and U.S. Pat. application Ser. No.60/331,951, filed Nov. 21, 2001, all of which are incorporated byreference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0003] This work was funded by grants from the National Institute ofHealth, P30 DK 47757-08 and P01 HL59407-02 and NIAID grant AI 49766-01.The United States government may have rights in this invention.

BACKGROUND OF THE INVENTION

[0004] Adenovirus is a double-stranded DNA virus with a genome size ofabout 36 kilobases (kb), which has been widely used for gene transferapplications due to its ability to achieve highly efficient genetransfer in a variety of target tissues and large transgene capacity.Conventionally, E1 genes of adenovirus are deleted and replaced with atransgene cassette consisting of the promoter of choice, cDNA sequenceof the gene of interest and a poly A signal, resulting in a replicationdefective recombinant virus.

[0005] Adenoviruses have a characteristic morphology with an icosahedralcapsid consisting of three major proteins, hexon (II), penton base (III)and a knobbed fibre (IV), along with a number of other minor proteins,VI, VIII, IX, IIIa and IVa2 [W. C. Russell, J. Gen Virol., 81:2573-2604(November 2000)]. The virus genome is a linear, double-stranded DNA witha terminal protein attached covalently to the 5′ termini, which haveinverted terminal repeats (ITRs). The virus DNA is intimately associatedwith the highly basic protein VII and a small peptide termed mu. Anotherprotein, V, is packaged with this DNA-protein complex and provides astructural link to the capsid via protein VI. The virus also contains avirus-encoded protease, which is necessary for processing of some of thestructural proteins to produce mature infectious virus.

[0006] Recombinant adenoviruses have been described for delivery ofmolecules to host cells. See, U.S. Pat. No. 6,083,716, which describesthe genome of two chimpanzee adenoviruses.

[0007] What is needed in the art are more effective vectors which avoidthe effect of pre-existing immunity to selected adenovirus serotypes inthe population and/or which are useful for repeat administration and fortiter boosting by second vaccination, if required.

SUMMARY OF THE INVENTION

[0008] The present invention provides simian adenovirus vectors andmethods of using same for delivery of heterologous molecules to desiredcells, in compositions, and for viral production. Also provided are theisolated nucleic acid sequences and amino acid sequences of six simianadenoviruses, vectors containing these sequences, and cell linesexpressing simian adenovirus genes.

[0009] The methods of the invention involve delivering one or moreselected heterologous gene(s) to a mammalian patient by administering avector of the invention. Because the various vector constructs arederived from simian rather than from human adenoviruses, the immunesystem of the non-simian human or veterinary patient is not primed torespond immediately to the vector as a foreign antigen. Use of thecompositions of this invention thus permits a more stable expression ofthe selected transgene when administered to a non-simian patient. Use ofthe compositions of this invention for vaccination permits presentationof a selected antigen for the elicitation of protective immuneresponses. Without wishing to be bound by theory, the ability of theadenoviruses of the invention to transduce human dendritic cells is atleast partially responsible for the ability of the recombinantconstructs of the invention to induce an immune response. Therecombinant simian adenoviruses of this invention may also be used forproducing heterologous gene products in vitro. Such gene products arethemselves useful in a variety for a variety of purposes such as aredescribed herein.

[0010] These and other embodiments and advantages of the invention aredescribed in more detail below.

BRIEF DESCRIPTION OF THE DRAWINGS

[0011]FIG. 1 summarizes the genetic organization of the chimpanzeeadenovirus C68 genome. In FIG. 1A the genome of the C68 chimpanzeeadenovirus is schematically represented by the box at the top. Theinverted terminal repeats are shaded black and the early regions areshaded gray. The arrowheads above the box indicate the direction ofexpression of the early genes. The line below the box represents thedivision of the genome into 100 map units. The arrows below the linerepresent the five late gene regions and the proteins encoded in eachregion. The numbers below the box or arrows indicate the start (promoteror initiation codon) and end (canonical PolyA signal) for each region. *represents the E2A late promoter. FIG. 1B illustrates the PstI clones;FIG. 1C illustrates the BamHI clones. FIG. 1D illustrates the HindIIIclones. For parts 1B-1D, the unshaded regions indicate that a fragmentwas cloned into a plasmid vector, as listed in Table 1, while the shadedregions indicate that the restriction fragment was not cloned. For eachsection the fragment name, alphabetical with A being the largestfragment, and the fragment size are listed above the box and thefragment end points are listed below the box.

[0012]FIG. 2 provides a multiple sequence alignment of hexon proteins.The deduced amino acid sequences of highly similar human adenovirushexons were compared with the chimpanzee adenovirus using CLUSTAL X.Serotypes and subgroups are indicated on the left margin, followed bythe residue number. The numbering refers to the amino acid position withrespect to the start of translation. Amino acids are shaded with respectto C68 [SEQ ID NO:47] to highlight sequence similarities (gray) andidentities (black). The seven hypervariable regions within loop domainsDE1 and FG1 are labeled along the bottom and correspond to the followingAd2 sequences in the alignment: HVR, 137-188; HVR2, 194-204; HVR3,222-229; HVR4, 258-271; HVR5, 278-294; HVR6, 316-327; and HVR7, 433-465.The GenBank accession numbers for the sequences shown are as follow:AAD03657 (Ad4, SEQ ID NO:48), S37216 (Ad 16, SEQ ID NO:49), S39298 (Ad3,SEQ ID NO:50), AAD03663 (Ad7, SEQ ID NO:51), and NP040525 (Ad2, SEQ IDNO:52).

[0013]FIG. 3 provides an alignment of the amino acid sequences of the L1and a portion of the L2 loops of the capsid protein hexon of thechimpanzee adenovirus C1 [SEQ ID NO:13], chimpanzee adenovirus C68(Pan-9) [SEQ ID NO:14], and the novel Pan5 [SEQ ID NO:15], Pan6 [SEQ IDNO: 16] and Pan7 [SEQ ID NO: 17] chimpanzee adenovirus sequences of theinvention. The intervening conserved region is part of the pedestaldomain conserved between adenovirus serotypes.

[0014]FIG. 4 provides an alignment of the amino acid sequences of thefiber knob domains of chimpanzee C68 (Pan-9) [SEQ ID NO:18], Pan-6 [SEQID NO:19], Pan-7 [SEQ ID NO:20], and Pan-5 [SEQ ID NO:21] and the humanadenoviruses serotypes 2 [SEQ ID NO:22] and 5 [SEQ ID NO:23].

DETAILED DESCRIPTION OF THE INVENTION

[0015] The present invention provides novel adenovirus-basedcompositions for use in delivering a heterologous molecule fortherapeutic or vaccine purposes. Such therapeutic or vaccinecompositions contain the adenoviral vectors carrying an insertedheterologous molecule.

[0016] The invention further provides novel nucleic acid and amino acidsequences from Ad Pan5 [SEQ ID NO:1-4, 15 and 21], Ad Pan6 [SEQ ID NO:5-8, 16, 19], and Ad serotype Pan7 [SEQ ID NO: 9-12, 17, 20], which wereoriginally isolated from chimpanzee lymph nodes. In several instancesthroughout the specification, these adenoviruses are alternativelytermed herein C5, C6 and C7, respectively. Also provided are sequencesfrom adenovirus SV1 [SEQ ID NO: 24-28], which was originally isolatedfrom the kidney cells of cynomolgus monkey. The invention also providessequences of adenoviruses SV-25 [SEQ ID NO:29-33] and SV-39 [SEQ ID NO:34-37], which were originally isolated from rhesus monkey kidney cells.Also, the invention provides packaging cell lines to produce vectorsbased upon these sequences for use in the in vitro production ofrecombinant proteins or fragments or other reagents. In addition, novelsequences of the invention are useful in providing the essential helperfunctions required for production of recombinant adeno-associated viral(AAV) vectors. Thus, the invention provides helper constructs, methodsand cell lines which use these sequences in such production methods.

[0017] The term “substantial homology” or “substantial similarity,” whenreferring to a nucleic acid or fragment thereof, indicates that, whenoptimally aligned with appropriate nucleotide insertions or deletionswith another nucleic acid (or its complementary strand), there isnucleotide sequence identity in at least about 95 to 99% of the alignedsequences.

[0018] The term “substantial homology” or “substantial similarity,” whenreferring to amino acids or fragments thereof, indicates that, whenoptimally aligned with appropriate amino acid insertions or deletionswith another amino acid (or its complementary strand), there is aminoacid sequence identity in at least about 95 to 99% of the alignedsequences. Preferably, the homology is over full-length sequence, or aprotein thereof, or a fragment thereof which is at least 8 amino acids,or more desirably, at least 15 amino acids in length. Examples ofsuitable fragments are described herein.

[0019] The term “percent sequence identity” or “identical” in thecontext of nucleic acid sequences refers to the residues in the twosequences that are the same when aligned for maximum correspondence. Thelength of sequence identity comparison may be over the full-length ofthe genome (e.g., about 36 kbp), the full-length of an open readingframe of a gene, protein, subunit, or enzyme [see, e.g., the tablesproviding the adenoviral coding regions], or a fragment of at leastabout 500 to 5000 nucleotides, is desired. However, identity amongsmaller fragments, e.g. of at least about nine nucleotides, usually atleast about 20 to 24 nucleotides, at least about 28 to 32 nucleotides,at least about 36 or more nucleotides, may also be desired. Similarly,“percent sequence identity” may be readily determined for amino acidsequences, over the full-length of a protein, or a fragment thereof.Suitably, a fragment is at least about 8 amino acids in length, and maybe up to about 700 amino acids. Examples of suitable fragments aredescribed herein.

[0020] Identity is readily determined using such algorithms and computerprograms as are defined herein at default settings. Preferably, suchidentity is over the full length of the protein, enzyme, subunit, orover a fragment of at least about 8 amino acids in length. However,identity may be based upon shorter regions, where suited to the use towhich the identical gene product is being put.

[0021] As described herein, alignments are performed using any of avariety of publicly or commercially available Multiple SequenceAlignment Programs, such as “Clustal W”, accessible through Web Serverson the internet. Alternatively, Vector NTI utilities are also used.There are also a number of algorithms known in the art that can be usedto measure nucleotide sequence identity, including those contained inthe programs described above. As another example, polynucleotidesequences can be compared using Fasta, a program in GCG Version 6.1.Fasta provides alignments and percent sequence identity of the regionsof the best overlap between the query and search sequences. Forinstance, percent sequence identity between nucleic acid sequences canbe determined using Fasta with its default parameters (a word size of 6and the NOPAM factor for the scoring matrix) as provided in GCG Version6.1, herein incorporated by reference. Similarly programs are availablefor performing amino acid alignments. Generally, these programs are usedat default settings, although one of skill in the art can alter thesesettings as needed. Alternatively, one of skill in the art can utilizeanother algorithm or computer program that provides at least the levelof identity or alignment as that provided by the referenced algorithmsand programs.

[0022] As used throughout this specification and the claims, the term“comprise” and its variants including, “comprises”, “comprising”, amongother variants, is inclusive of other components, elements, integers,steps and the like. The term “consists of” or “consisting of” areexclusive of other components, elements, integers, steps and the like.

[0023] I. The Simian Adenovirus Sequences

[0024] A variety of sources of chimpanzee adenovirus sequences areavailable from the American Type Culture Collection, 10801 UniversityBoulevard, Manassas, Va. 20110-2209, and other sources. Desirablechimpanzee strains Pan 5 [ATCC VR-591], Pan 6 [ATCC VR-592], and Pan 7[ATCC VR-593]. Particularly desirable chimpanzee adenovirus strains, arechimpanzee adenovirus strain Bertha or C1 [ATCC Accession No. VR-20] andchimpanzee adenovirus, strain Pan 9 or CV68 [ATCC VR-594]. Forconvenience, the virus CV68 is referred to throughout this specificationas “C68”. The viruses were originally isolated from feces [C1, Rowe etal, Proc. Soc. Exp. Med., 91:260 (1956)] or mesenteric lymph node [C68,Basnight et al, Am. J Epidemiol., 94:166 (1971)] of infectedchimpanzees. The sequences of these strains, and the location of theadenovirus genes E1a, E1b, E2a, E2b, E3, E4, L1, L2, L3, L4 and L5 areprovided in U.S. Pat. No. 6,083,716, which is incorporated by referenceherein. Optionally, non-chimpanzee simian adenoviral sequences may beused in preparing the recombinant vectors of the invention. Suchnon-chimpanzee adenovirus include those obtained from baboon adenovirusstrains [e.g., ATCC VR-275], adenovirus strains isolated from rhesusmonkeys [e.g., ATCC VR-209, ATCC VR-275, ATCC VR-353, ATCC VR-355], andadenovirus strains isolated from African green monkeys [e.g., ATCCVR-541; ATCC VR-941; ATCC VR-942; ATCC VR-943].

[0025] In one embodiment, the recombinant chimpanzee (or other simian)adenoviruses described herein may contain adenoviral sequences derivedfrom one, more than one simian adenoviral strain. These sequences may beobtained from natural sources, produced recombinantly, synthetically, orby other genetic engineering or chemical methods.

[0026] The recombinant simian adenoviruses useful in this invention areviral particles that are composed of recombinant simian adenovirusessequences carrying a heterologous molecule and/or simian adenoviruscapsid proteins. These simian adenoviruses, and particularly thechimpanzee C68 and C1 sequences, are also useful in forming hybridvectors with other simian and non-simian adenoviruses, and in formingpseudotyped recombinant viruses, i.e., recombinant viruses with anadenoviral vector carrying a heterologous molecule which is packaged ina heterologous capsid protein of simian origin.

[0027] In certain embodiments, the invention provides nucleic acidsequences and amino acid sequences of Pan5, Pan6, Pan7, SV1, SV25 andSV39, which are isolated from the other viral material with which theyare associated in nature.

[0028] A. Nucleic Acid Sequences

[0029] The Pan5 nucleic acid sequences of the invention includenucleotides 1 to 36462 of SEQ ID NO:1. The Pan6 nucleic acid sequencesof the invention include nucleotides 1 to 36604 of SEQ ID NO: 5. ThePan7 nucleic acid sequences of the invention include nucleotides 1 to36535 of SEQ ID NO: 9. The SV1 nucleic acid sequences of the inventioninclude nucleotides 1 to 34264 of SEQ ID NO: 24. The SV25 nucleic acidsequences of the invention include nucleotides 1 to 31044 of SEQ ID NO:29. The SV39 nucleic acid sequences of the invention include nucleotides1 to 34115 of SEQ ID NO: 34. See, Sequence Listing, which isincorporated by reference herein.

[0030] The nucleic acid sequences of the invention further encompass thestrand which is complementary to the sequences of SEQ ID NO: 5, 9, 24,29 and 34, as well as the RNA and cDNA sequences corresponding to thesequences of these sequences figures and their complementary strands.Further included in this invention are nucleic acid sequences which aregreater than 95 to 98%, and more preferably about 99 to 99.9% homologousor identical to the Sequence Listing. Also included in the nucleic acidsequences of the invention are natural variants and engineeredmodifications of the sequences provided in SEQ ID NO: 5, 9, 24, 29 and34 and their complementary strands. Such modifications include, forexample, labels that are known in the art, methylation, and substitutionof one or more of the naturally occurring nucleotides with a degeneratenucleotide.

[0031] The invention further encompasses fragments of the sequences ofPan5, Pan6, Pan7, SV1, SV25 and SV39, their complementary strand, cDNAand RNA complementary thereto. Suitable fragments are at least 15nucleotides in length, and encompass functional fragments, i.e.,fragments which are of biological interest. For example, a functionalfragment can express a desired adenoviral product or may be useful inproduction of recombinant viral vectors. Such fragments include the genesequences and fragments listed in the tables below.

[0032] The following tables provide the transcript regions and openreading frames in the simian adenovirus sequences of the invention. Forcertain genes, the transcripts and open reading frames (ORFs) arelocated on the strand complementary to that presented in SEQ ID NO: 5,9, 24, 29 and 34. See, e.g., E2b, E4 and E2a. The calculated molecularweights of the encoded proteins are also shown. Note that the E1 a openreading frame Pan5 [nt 576-1436 of SEQ ID NO:1], Pan6 [nt 576 to 1437 ofSEQ ID NO: 5] and Pan7 [nt 576 to 1437 of SEQ ID NO: 9] contain internalsplice sites. These splice sites are noted in the following tables. AdPan-5 [SEQ ID NO: 1] Start End M.W. Regions (nt) (nt) (Daltons) ITR 1120 — E1a Transcript 478 — 13S 576-664, 1233-1436 28120 12S 576-1046,1233-1436 24389 9S 576-644, 1233-1436 9962 Transcript 1516 — E1bTranscript 1552 — Small T 1599 2171 22317 Large T 1904 3412 55595 IX3492 3920 14427 Transcript 3959 — E2b Transcript 10349 — PTP 10349 845172930 Polymerase 8448 5083 127237 IVa2 5604 3980 50466 Transcript 396028.1 kD 5155 5979 28141 Agnoprotein 7864 8580 25755 L1 Transcript 10849— 52/55D 10851 12025 IIIa 12050 13819 65669 Transcript 13832 —Transcript 13894 — L2 Penton 13898 15490 59292 VII 15494 16078 21478 V16123 17166 39568 Mu 17189 17422 8524 Transcript 17442 — Transcript17488 — L3 VI 17491 18222 26192 Hexon 18315 21116 104874 Endoprotease20989 21783 28304 Transcript 21811 — E2a Transcript 26782 — DBP 2338621845 57358 Transcript 21788 — L4 Transcript 23406 — 100 kD 23412 2580588223 33 kD homolog 25525 26356 24538 VIII 26428 27111 24768 Transcript27421 — E3 Transcript 26788 — Orf #1 27112 27432 12098 Orf #2 2738628012 23040 Orf #3 27994 28527 19525 Orf #4 28557 29156 22567 Orf #529169 29783 22267 Orf #6 29798 30673 31458 Orf #7 30681 30956 10477 Orf#8 30962 31396 16523 Orf #9 31389 31796 15236 Transcript 31837 — L5Transcript 32032 — Fiber 32035 33372 47670 Transcript 33443 — E4Transcript 36135 — Orf 7 33710 33462 9191 Orf 6 34615 33710 35005 Orf 434886 34521 13878 Orf 3 35249 34896 13641 Orf 2 35635 35246 14584 Orf 136050 35676 13772 Transcript 33437 — ITR 36343 36462 —

[0033] Ad Pan-6 [SEQ ID NO: 5] Start End M.W. Regions (nt) (nt)(Daltons) ITR 1 123 — E1a Transcript 478 — 13S 576-1143, 1229-1437 2829112S 576-1050, 1229-1437 24634 9S 576-645, 1229-1437 10102 Transcript1516 — E1b Transcript 1553 — Small T 1600 2172 22315 LargeT 1905 341355594 IX 3498 3926 14427 Transcript 3965 — E2b Transcript 10341 — PTP10340 8451 72570 Polymerase 8445 5089 126907 IVa2 5610 3986 50452Transcript 3966 — L1 Transcript 10838 — 52/55 KD 10840 12012 44205 IIIa12036 13799 65460 Transcript 13812 — 28.1 kd 5161 5985 28012 Agnoprotein7870 8580 25382 L2 Transcript 13874 — Penton 13878 15467 59314 VII 1547116055 21508 V 16100 17137 39388 Mu 17160 17393 8506 Transcript 17415 —L3 Transcript 17466 — VI 17469 18188 25860 Hexon 18284 21112 106132Endoprotease 21134 21754 23445 Transcript 21803 — E2a Transcript 26780 —DBP 23375 21837 57299 Tanscript 21780 — L4 Transcript 23398 — 100 kD23404 25806 88577 33 kD homolog 25523 26357 24609 VIII 26426 27109 24749Transcript 27419 — E3 Transcript 26786 — Orf #1 27110 27430 12098 Orf #227384 28007 22880 Orf #3 27989 28519 19460 Orf #4 28553 29236 25403 Orf#5 29249 29860 22350 Orf #6 29875 30741 31028 Orf #7 30749 31024 10469Orf #8 31030 31464 16540 Orf #9 31457 31864 15264 Transcript 31907 — L5Transcript 32159 Fiber 32162 33493 47364 Transcript 33574 — E4Transcript 36276 — Orf 7 33841 33593 9177 Orf 6 34746 33841 35094 Orf 435017 34652 13937 Orf 3 35380 35027 13627 Orf 2 35766 35377 14727 Orf 136181 35807 13739 Transcript 33558 — ITR 36482 36604 —

[0034] Ad Pan-7 [SEQ ID NO: 9] Start End M.W. Regions (nt) (nt)(Daltons) ITR 1 132 — E1a Transcript 478 — 13S 576-1143, 1229-1437 2821812S 576-1050, 1229-1437 24561 9S 576-645, 10102 1229-1437 Transcript1516 — E1b Transcript 1553 — Small T 1600 2178 22559 LargeT 1905 341955698 IVa2 3992 5616 50210 Transcript 3971 — E2b Transcript 10341 — PTP10340 8457 72297 Polymerase 8451 5095 126994 IX 3504 3932 14441Transcript 3972 — 28.1 kD 5167 5991 28028 Agnoprotein 7876 8586 25424 L1Transcript 10834 52/55 kD 10836 12011 44302 IIIa 12035 13795 65339Transcript 13808 — L2 Transcript 13870 — Penton 13874 15469 59494 VII15473 16057 21339 V 16102 17139 39414 Mu 17167 17400 8506 Transcript17420 — L3 Transcript 17467 — VI 17470 18198 26105 Hexon 18288 21086104763 Endoprotease 21106 21732 23620 Transcript 21781 — E2a Transcript26764 — DBP 23353 21815 57199 Transcript 21755 — L4 Transcript 23370 —100 kD 23376 25781 88520 33 kD 25489 26338 25155 homolog VIII 2641027093 24749 Transcript 27403 — E3 Transcript 26770 — Orf #1 27094 2741412056 Orf #2 27368 27988 22667 Orf #3 27970 28500 19462 Orf #4 2853029150 22999 Orf #5 29163 29777 22224 Orf #6 29792 30679 32153 Orf #730687 30962 10511 Orf #8 30968 31399 16388 Orf #9 31392 31799 15205Transcript 31842 — L5 Transcript 32091 — Fiber 32094 33425 47344Transcript 33517 — E4 Transcript 36208 — Orf 7 33784 33536 9191 Orf 634689 33784 35063 Orf 4 34960 34595 13879 Orf 3 35323 34970 13641 Orf 235709 35320 14644 Orf 1 36123 35749 13746 Transcript 33501 — ITR 3640436535 —

[0035] Ad SV-1 Ad SV-25 Ad SV-39 [SEQ ID NO: 24] [SEQ ID NO: 29] [SEQ IDNO: 34] Region Start End Start End Start End ITR 1 106 1 133 1 150 E1a352 1120 — — 404 1409 E1b 1301 2891 359 2273 1518 3877 E2b 9257 28829087 2754 10143 3868 E2a 24415 20281 24034 20086 25381 21228 E3 2497427886 24791 25792 25790 29335 E4 33498 30881 30696 28163 33896 31157 ITR34145 34264 30912 31044 33966 34115 ITR 1 106 1 133 1 150 L1 9513 123769343 12206 10416 13383 L2 12453 15858 12283 15696 13444 16877 L3 1591020270 15748 20080 17783 21192 L4 21715 25603 21526 25420 22659 26427 L528059 30899 25320 28172 29513 31170 ITR 34145 34264 30912 31044 3396634115

[0036] Ad SV-1, SEQ ID NO: 24 Protein Start End M.W. ITR 1 106 — E1a 13S459 953 18039 12S E1b Small T LargeT 1301 2413 42293 IX 2391 2885 16882E2b IVa2 4354 2924 54087 Polymerase 6750 4027 102883 PTP 9257 7371 72413Agno-protein 6850 7455 20984 L1 52/55 kD 9515 10642 42675 IIIa 1066312372 636568 L2 Penton 12454 13965 56725 VII 13968 14531 20397 V 1458815625 39374 Mu 15645 15857 7568 L3 VI 15911 16753 30418 Hexon 1684119636 104494 Endoprotease 19645 20262 23407 2a DBP 21700 20312 52107 L4100 kD 21721 24009 85508 VIII 24591 25292 25390 E3 Orf #1 25292 2560911950 Orf #2 25563 26081 18940 Orf #3 26084 26893 30452 Orf #4 2690827180 10232 Orf #5 27177 17512 12640 Orf #6 27505 27873 13639 L5 Fiber#2 28059 29150 39472 Fiber #1 29183 30867 61128 E4 Orf 7 31098 308927837 Orf 6 31982 31122 33921 Orf 4 32277 31915 14338 Orf 3 32629 3227913386 Orf 2 33018 32626 14753 Orf 1 33423 33043 14301 ITR 34145 34264

[0037] Ad SV-25, Ad SV-39, SEQ ID NO: 29 SEQ ID NO: 34 protein Start EndM.W. Start End M.W. ITR 1 133 — 1 150 — E1a 13S 492 1355 28585 12S 4921355 25003 E1b Small T 478 1030 20274 1518 2075 21652 Large T 829 224452310 1823 3349 55534 IX 2306 2716 13854 3434 3844 14075 E2b IVa2 42082755 54675 3912 5141 46164 Poly- 6581 3858 102839 7753 5033 103988merase PTP 9087 7207 71326 10143 8335 69274 Agno- 6681 7139 16025 — — —protein L1 52/55 9345 10472 42703 10418 11608 44232 kD IIIa 10493 1220263598 11574 13364 66078 L2 Penton 12284 13801 56949 13448 14959 56292VII 13806 14369 20369 14960 15517 20374 V 14426 15463 39289 15567 1662839676 Mu 15483 15695 7598 16650 16871 7497 L3 VI 15749 16591 30347 1692517695 28043 Hexon 16681 19446 104035 17785 20538 102579 Endo- 1945520072 23338 20573 21181 22716 protease 2a DBP 21511 20123 52189 2263121231 53160 L4 100 kD 21532 23829 85970 22659 25355 100362 VIII 2440825109 25347 25410 26108 25229 E3 Orf #1 25109 25426 11890 26375 2748442257 Orf #2 27580 28357 29785 Orf #3 28370 28645 10514 Orf #4 2886329333 18835 Orf #5 Orf #6 L5 Fiber #2 25380 26423 37529 Fiber #1 2645728136 60707 29515 31116 56382 E4 Orf 7 31441 31118 11856 Orf 6 2925528395 33905 32292 31438 33437 Orf 4 29550 29188 14399 32587 32222 13997Orf 3 29902 29552 13284 32954 32607 13353 Orf 2 30291 29899 14853 3334832959 14821 Orf 1 30316 30696 14301 33764 33378 14235 ITR 30912 3104433966 34115

[0038] The simian adenoviruses described herein are useful astherapeutic agents and in construction of a variety of vector systemsand host cells. As used herein, a vector includes any suitable nucleicacid molecule including, naked DNA, a plasmid, a virus, a cosmid, or anepisome. These sequences and products may be used alone or incombination with other adenoviral sequences or fragments, or incombination with elements from other adenoviral or non-adenoviralsequences. The adenoviral sequences of the invention are also useful asantisense delivery vectors, gene therapy vectors, or vaccine vectors.Thus, the invention further provides nucleic acid molecules, genedelivery vectors, and host cells that contain the Ad sequences of theinvention.

[0039] For example, the invention encompasses a nucleic acid moleculecontaining simian Ad ITR sequences of the invention. In another example,the invention provides a nucleic acid molecule containing simian Adsequences of the invention encoding a desired Ad gene product. Stillother nucleic acid molecule constructed using the sequences of theinvention will be readily apparent to one of skill in the art, in viewof the information provided herein.

[0040] In one embodiment, the simian Ad gene regions identified hereinmay be used in a variety of vectors for delivery of a heterologousmolecule to a cell. For example, vectors are generated for expression ofan adenoviral capsid protein (or fragment thereof) for purposes ofgenerating a viral vector in a packaging host cell. Such vectors may bedesigned for expression in trans. Alternatively, such vectors aredesigned to provide cells which stably contain sequences which expressdesired adenoviral functions, e.g., one or more of E1a, E1b, theterminal repeat sequences, E2a, E2b, E4, E40RF6 region.

[0041] In addition, the adenoviral gene sequences and fragments thereofare useful for providing the helper functions necessary for productionof helper-dependent viruses (e.g., adenoviral vectors deleted ofessential functions or adeno-associated viruses (AAV)). For suchproduction methods, the simian adenoviral sequences of the invention areutilized in such a method in a manner similar to those described for thehuman Ad. However, due to the differences in sequences between thesimian adenoviral sequences of the invention and those of human Ad, theuse of the sequences of the invention essentially eliminate thepossibility of homologous recombination with helper functions in a hostcell carrying human Ad E1 functions, e.g., 293 cells, which may produceinfectious adenoviral contaminants during rAAV production.

[0042] Methods of producing rAAV using adenoviral helper functions havebeen described at length in the literature with human adenoviralserotypes. See, e.g., U.S. Pat. No. 6,258,595, U.S. Pat. No. 6,083,716,and the references cited therein. See, also, U.S. Pat. No. 5,871,982; WO99/14354; WO 99/15685; WO 99/47691. These methods may also be used inproduction of non-human serotype AAV, including non-human primate AAVserotypes. The simian adenoviral gene sequences of the invention whichprovide the necessary helper functions (e.g., E1a, E1b, E2a and/or E4ORF6) can be particularly useful in providing the necessary adenoviralfunction while minimizing or eliminating the possibility ofrecombination with any other adenoviruses present in the rAAV-packagingcell which are typically of human origin. Thus, selected genes or openreading frames of the adenoviral sequences of the invention may beutilized in these rAAV production methods.

[0043] Alternatively, recombinant adenoviral simian vectors of theinvention may be utilized in these methods. Such recombinant adenoviralsimian vectors may include, e.g., a hybrid chimp Ad/AAV in which chimpAd sequences flank a rAAV expression cassette composed of, e.g., AAV 3′and/or 5′ ITRs and a transgene under the control of regulatory sequenceswhich control its expression. One of skill in the art will recognizethat still other simian adenoviral vectors and/or gene sequences of theinvention will be useful for production of rAAV and other virusesdependent upon adenoviral helper.

[0044] In still another embodiment, nucleic acid molecules are designedfor delivery and expression of selected adenoviral gene products in ahost cell to achieve a desired physiologic effect. For example, anucleic acid molecule containing sequences encoding an adenovirus E1aprotein of the invention may be delivered to a subject for use as acancer therapeutic. Optionally, such a molecule is formulated in alipid-based carrier and preferentially targets cancer cells. Such aformulation may be combined with other cancer therapeutics (e.g.,cisplatin, taxol, or the like). Still other uses for the adenoviralsequences provided herein will be readily apparent to one of skill inthe art.

[0045] In addition, one of skill in the art will readily understand thatthe Ad sequences of the invention can be readily adapted for use for avariety of viral and non-viral vector systems for in vitro, ex vivo orin vivo delivery of therapeutic and immunogenic molecules. For example,the Pan5, Pan6, Pan7, SV1, SV25 and/or SV39 simian Ad genomes of theinvention can be utilized in a variety of rAd and non-rAd vectorsystems. Such vectors systems may include, e.g., plasmids, lentiviruses,retroviruses, poxviruses, vaccinia viruses, and adeno-associated viralsystems, among others. Selection of these vector systems is not alimitation of the present invention.

[0046] The invention further provides molecules useful for production ofthe simian and simian-derived proteins of the invention. Such moleculeswhich carry polynucleotides including the simian Ad DNA sequences of theinvention can be in the form of naked DNA, a plasmid, a virus or anyother genetic element.

[0047] B. Simian Adenoviral Proteins of the Invention

[0048] The invention further provides gene products of the aboveadenoviruses, such as proteins, enzymes, and fragments thereof, whichare encoded by the adenoviral nucleic acids of the invention. Theinvention further encompasses Pan5, Pan6 and Pan7, SV1, SV25 and SV39proteins, enzymes, and fragments thereof, having the amino acidsequences encoded by these nucleic acid sequences which are generated byother methods. Such proteins include those encoded by the open readingframes identified in the tables above, in FIGS. 1 and 2, and fragmentsthereof.

[0049] Thus, in one aspect, the invention provides unique simianadenoviral proteins which are substantially pure, i.e., are free ofother viral and proteinaceous proteins. Preferably, these proteins areat least 10% homogeneous, more preferably 60% homogeneous, and mostpreferably 95% homogeneous.

[0050] In one embodiment, the invention provides unique simian-derivedcapsid proteins. As used herein, a simian-derived capsid proteinincludes any adenoviral capsid protein that contains a Pan5, Pan6, Pan7,SV1, SV25 or SV39 capsid protein or a fragment thereof, as definedabove, including, without limitation, chimeric capsid proteins, fusionproteins, artificial capsid proteins, synthetic capsid proteins, andrecombinantly capsid proteins, without limitation to means of generatingthese proteins.

[0051] Suitably, these simian-derived capsid proteins contain one ormore Pan5, Pan6, Pan7, SV1, SV25 or SV39 regions or fragments thereof(e.g., a hexon, penton, fiber or fragment thereof) in combination withcapsid regions or fragments thereof of different adenoviral serotypes,or modified simian capsid proteins or fragments, as described herein. A“modification of a capsid protein associated with altered tropism” asused herein includes an altered capsid protein, i.e, a penton, hexon orfiber protein region, or fragment thereof, such as the knob domain ofthe fiber region, or a polynucleotide encoding same, such thatspecificity is altered. The simian-derived capsid may be constructedwith one or more of the simian Ad of the invention or another Adserotypes which may be of human or non-human origin. Such Ad may beobtained from a variety of sources including the ATCC, commercial andacademic sources, or the sequences of the Ad may be obtained fromGenBank or other suitable sources.

[0052] The amino acid sequences of the simian adenoviruses pentonproteins of the invention are provided herein. The AdPan5 penton proteinis provided in SEQ ID NO:2. The AdPan7 penton is provided in SEQ IDNO:6. The AdPan6 penton is provided in SEQ ID NO:10. The SV1 penton isprovided in SEQ ID NO:25. The SV25 penton protein is provided in SEQ IDNO:30. The SV39 penton is provided in SEQ ID NO:35. Suitably, any ofthese penton proteins, or unique fragments thereof, may be utilized fora variety of purposes. Examples of suitable fragments include the pentonhaving N-terminal and/or C-terminal truncations of about 50, 100, 150,or 200 amino acids, based upon the amino acid numbering provided aboveand in SEQ ID NO:2; SEQ ID NO:6; SEQ ID NO:25; SEQ ID NO:30, or SEQ IDNO:35. Other suitable fragments include shorter internal, C-terminal, orN-terminal fragments. Further, the penton protein may be modified for avariety of purposes known to those of skill in the art.

[0053] The invention further provides the amino acid sequences of thehexon protein of Pan5 [SEQ ID NO:3], Pan6 [SEQ ID NO:7], Pan 7 [SEQ IDNO:1 1], SV1 [SEQ ID NO:26], SV25 [SEQ ID NO:31], and/or SV39 [SEQ IDNO:36]. Suitably, this hexon protein, or unique fragments thereof, maybe utilized for a variety of purposes. Examples of suitable fragmentsinclude the hexon having N-terminal and/or C-terminal truncations ofabout 50, 100, 150, 200, 300, 400, or 500 amino acids, based upon theamino acid numbering provided above and in SEQ ID NO: 3, 7, 11, 26, 31and 36. Other suitable fragments include shorter internal, C-terminal,or N-terminal fragments. For example, one suitable fragment the loopregion (domain) of the hexon protein, designated DE1 and FG1, or ahypervariable region thereof. Such fragments include the regionsspanning amino acid residues about 125 to 443; about 138 to 441, orsmaller fragments, such as those spanning about residue 138 to residue163; about 170 to about 176; about 195 to about 203; about 233 to about246; about 253 to about 264; about 287 to about 297; and about 404 toabout 430 of the simian hexon proteins, with reference to SEQ ID NO: 3,7, 11, 26, 31 or 36. Other suitable fragments may be readily identifiedby one of skill in the art. Further, the hexon protein may be modifiedfor a variety of purposes known to those of skill in the art. Becausethe hexon protein is the determinant for serotype of an adenovirus, suchartificial hexon proteins would result in adenoviruses having artificialserotypes. Other artificial capsid proteins can also be constructedusing the chimp Ad penton sequences and/or fiber sequences of theinvention and/or fragments thereof.

[0054] In one example, it may be desirable to generate an adenovirushaving an altered hexon protein utilizing the sequences of a hexonprotein of the invention. One suitable method for altering hexonproteins is described in U.S. Pat. No. 5,922,315, which is incorporatedby reference. In this method, at least one loop region of the adenovirushexon is changed with at least one loop region of another adenovirusserotype. Thus, at least one loop region of such an altered adenovirushexon protein is a simian Ad hexon loop region of the invention (e.g.Pan7). In one embodiment, a loop region of the Pan7 hexon protein isreplaced by a loop region from another adenovirus serotype. In anotherembodiment, the loop region of the Pan7 hexon is used to replace a loopregion from another adenovirus serotype. Suitable adenovirus serotypesmay be readily selected from among human and non-human serotypes, asdescribed herein. Pan7 is selected for purposes of illustration only;the other simian Ad hexon proteins of the invention may be similarlyaltered, or used to alter another Ad hexon. The selection of a suitableserotype is not a limitation of the present invention. Still other usesfor the hexon protein sequences of the invention will be readilyapparent to those of skill in the art.

[0055] The invention further encompasses the fiber proteins of thesimian adenoviruses of the invention. The fiber protein of AdPan 5 hasthe amino acid sequence of SEQ ID NO:4. The fiber protein AdPan6 has theamino acid sequence of SEQ ID NO: 8. The fiber protein of AdPan7 has theamino acid sequence of SEQ ID NO: 12. SV-1 has two fiber proteins; fiber2 has the amino acid sequence of SEQ ID NO:27 and fiber 1 has the aminoacid sequence of SEQ ID NO:28. SV-25 also has two fiber proteins; fiber2 has the amino acid sequence of SEQ ID NO:32 and fiber 1 has the aminoacid sequence of SEQ ID NO:33. The fiber protein of SV-39 has the aminoacid sequence of SEQ ID NO:37.

[0056] Suitably, this fiber protein, or unique fragments thereof, may beutilized for a variety of purposes. One suitable fragment is the fiberknob, which spans about amino acids 247 to 425 of SEQ ID NO: 4, 8, 12,28, 32, 33 and 37. See FIG. 2. Examples of other suitable fragmentsinclude the fiber having N-terminal and/or C-terminal truncations ofabout 50, 100, 150, or 200 amino acids, based upon the amino acidnumbering provided above and in SEQ ID NO: 4, 8, 12, 28, 32, 33 and 37.Still other suitable fragments include internal fragments. Further, thefiber protein may be modified using a variety of techniques known tothose of skill in the art.

[0057] The invention further encompasses unique fragments of theproteins of the invention which are at least 8 amino acids in length.However, fragments of other desired lengths can be readily utilized. Inaddition, the invention encompasses such modifications as may beintroduced to enhance yield and/or expression of a Pan5, Pan6, Pan7,SV1, SV25 or SV39 gene product, e.g., construction of a fusion moleculein which all or a fragment of the Pan5, Pan6, Pan7, SV1, SV25 or SV39gene product is fused (either directly or via a linker) with a fusionpartner to enhance. Other suitable modifications include, withoutlimitation, truncation of a coding region (e.g., a protein or enzyme) toeliminate a pre- or pro-protein ordinarily cleaved and to provide themature protein or enzyme and/or mutation of a coding region to provide asecretable gene product. Still other modifications will be readilyapparent to one of skill in the art. The invention further encompassesproteins having at least about 95% to 99% identity to the Pan5, Pan6,Pan7, SV1, SV25 or SV39 proteins provided herein.

[0058] As described herein, vectors of the invention containing theadenoviral capsid proteins of the invention are particularly well suitedfor use in applications in which the neutralizing antibodies diminishthe effectiveness of other Ad serotype based vectors, as well as otherviral vectors. The rAd vectors of the invention are particularlyadvantageous in readministration for repeat gene therapy or for boostingimmune response (vaccine titers).

[0059] Under certain circumstances, it may be desirable to use one ormore of the Pan5, Pan6, Pan7, SV1, SV25 and/or SV39 gene products (e.g.,a capsid protein or a fragment thereof) to generate an antibody. Theterm “an antibody,” as used herein, refers to an immunoglobulin moleculewhich is able to specifically bind to an epitope. Thus, the antibodiesof the invention bind, preferably specifically and withoutcross-reactivity, to a Pan5, Pan6, Pan7, SV1, SV25 or SV39 epitope. Theantibodies in the present invention exist in a variety of formsincluding, for example, high affinity polyclonal antibodies, monoclonalantibodies, synthetic antibodies, chimeric antibodies, recombinantantibodies and humanized antibodies. Such antibodies originate fromimmunoglobulin classes IgG, IgM, IgA, IgD and IgE.

[0060] Such antibodies may be generated using any of a number of methodsknow in the art. Suitable antibodies may be generated by well-knownconventional techniques, e.g. Kohler and Milstein and the many knownmodifications thereof. Similarly desirable high titer antibodies aregenerated by applying known recombinant techniques to the monoclonal orpolyclonal antibodies developed to these antigens [see, e.g., PCT PatentApplication No. PCT/GB85/00392; British Patent Application PublicationNo. GB2188638A; Amit et al., 1986 Science, 233:747-753; Queen et al.,1989 Proc. Nat'l. Acad. Sci. USA, 86:10029-10033; PCT Patent ApplicationNo. PCT/WO9007861; and Riechmann et al., Nature, 332:323-327 (1988);Huse et al, 1988a Science, 246:1275-1281]. Alternatively, antibodies canbe produced by manipulating the complementarity determining regions ofanimal or human antibodies to the antigen of this invention. See, e.g.,E. Mark and Padlin, “Humanization of Monoclonal Antibodies”, Chapter 4,The Handbook of Experimental Pharmacology, Vol. 113, The Pharmacology ofMonoclonal Antibodies, Springer-Verlag (June, 1994); Harlow et al.,1999, Using Antibodies: A Laboratory Manual, Cold Spring HarborLaboratory Press, NY; Harlow et al., 1989, Antibodies: A LaboratoryManual, Cold Spring Harbor, N.Y.; Houston et al., 1988, Proc. Natl.Acad. Sci. USA 85:5879-5883; and Bird et al., 1988, Science 242:423-426.Further provided by the present invention are anti-idiotype antibodies(Ab2) and anti-anti-idiotype antibodies (Ab3). See, e.g., M. Wettendorffet al., “Modulation of anti-tumor immunity by anti-idiotypicantibodies.” In Idiotypic Network and Diseases, ed. by J. Cerny and J.Hiernaux, 1990 J Am. Soc. Microbiol., Washington D.C.: pp. 203-229].These anti-idiotype and anti-anti-idiotype antibodies are produced usingtechniques well known to those of skill in the art. These antibodies maybe used for a variety of purposes, including diagnostic and clinicalmethods and kits.

[0061] Under certain circumstances, it may be desirable to introduce adetectable label or a tag onto a Pan5, Pan6, Pan7, SV1, SV25 or SV39gene product, antibody or other construct of the invention. As usedherein, a detectable label is a molecule which is capable, alone or uponinteraction with another molecule, of providing a detectable signal.Most desirably, the label is detectable visually, e.g. by fluorescence,for ready use in immunohistochemical analyses or immunofluorescentmicroscopy. For example, suitable labels include fluoresceinisothiocyanate (FITC), phycoerythrin (PE), allophycocyanin (APC),coriphosphine-O (CPO) or tandem dyes, PE-cyanin-5 (PC5), and PE-TexasRed (ECD). All of these fluorescent dyes are commercially available, andtheir uses known to the art. Other useful labels include a colloidalgold label. Still other useful labels include radioactive compounds orelements. Additionally, labels include a variety of enzyme systems thatoperate to reveal a calorimetric signal in an assay, e.g., glucoseoxidase (which uses glucose as a substrate) releases peroxide as aproduct which in the presence of peroxidase and a hydrogen donor such astetramethyl benzidine (TMB) produces an oxidized TMB that is seen as ablue color. Other examples include horseradish peroxidase (HRP) oralkaline phosphatase (AP), and hexokinase in conjunction withglucose-6-phosphate dehydrogenase which reacts with ATP, glucose, andAND+ to yield, among other products, NADH that is detected as increasedabsorbance at 340 nm wavelength.

[0062] Other label systems that are utilized in the methods of thisinvention are detectable by other means, e.g., colored latexmicroparticles [Bangs Laboratories, Indiana] in which a dye is embeddedare used in place of enzymes to form conjugates with the targetsequences provide a visual signal indicative of the presence of theresulting complex in applicable assays.

[0063] Methods for coupling or associating the label with a desiredmolecule are similarly conventional and known to those of skill in theart. Known methods of label attachment are described [see, for example,Handbook of Fluorescent probes and Research Chemicals, 6th Ed., R. P. M.Haugland, Molecular Probes, Inc., Eugene, Oreg., 1996; Pierce Catalogand Handbook, Life Science and Analytical Research Products, PierceChemical Company, Rockford, Ill., 1994/1995]. Thus, selection of thelabel and coupling methods do not limit this invention.

[0064] The sequences, proteins, and fragments of the invention may beproduced by any suitable means, including recombinant production,chemical synthesis, or other synthetic means. Suitable productiontechniques are well known to those of skill in the art. See, e.g.,Sambrook et al, Molecular Cloning: A Laboratory Manual, Cold SpringHarbor Press (Cold Spring Harbor, N.Y.). Alternatively, peptides canalso be synthesized by the well known solid phase peptide synthesismethods (Merrifield, J. Am. Chem. Soc., 85:2149 (1962); Stewart andYoung, Solid Phase Peptide Synthesis (Freeman, San Francisco, 1969) pp.27-62). These and other suitable production methods are within theknowledge of those of skill in the art and are not a limitation of thepresent invention.

[0065] In addition, one of skill in the art will readily understand thatthe Ad sequences of the invention can be readily adapted for use for avariety of viral and non-viral vector systems for in vitro, ex vivo orin vivo delivery of therapeutic and immunogenic molecules. For example,in one embodiment, the simian Ad capsid proteins and other simianadenovirus proteins described herein are used for non-viral,protein-based delivery of genes, proteins, and other desirablediagnostic, therapeutic and immunogenic molecules. In one suchembodiment, a protein of the invention is linked, directly orindirectly, to a molecule for targeting to cells with a receptor foradenoviruses. Preferably, a capsid protein such as a hexon, penton,fiber or a fragment thereof having a ligand for a cell surface receptoris selected for such targeting. Suitable molecules for delivery areselected from among the therapeutic molecules described herein and theirgene products. A variety of linkers including, lipids, polyLys, and thelike may be utilized as linkers. For example, the simian penton proteinmay be readily utilized for such a purpose by production of a fusionprotein using the simian penton sequences in a manner analogous to thatdescribed in Medina-Kauwe LK, et al, Gene Ther. May 8, 2001;(10):795-803 and Medina-Kauwe LK, et al, Gene Ther. Dec. 8, 2001; (23):1753-1761. Alternatively, the amino acid sequences of simian Ad proteinIX may be utilized for targeting vectors to a cell surface receptor, asdescribed in US Patent Appln 20010047081. Suitable ligands include aCD40 antigen, an RGD-containing or polylysine-containing sequence, andthe like. Still other simian Ad proteins, including, e.g., the hexonprotein and/or the fiber protein, may be used for used for these andsimilar purposes.

[0066] Still other adenoviral proteins of the invention may be used asalone, or in combination with other adenoviral protein, for a variety ofpurposes which will be readily apparent to one of skill in the art. Inaddition, still other uses for the adenoviral proteins of the inventionwill be readily apparent to one of skill in the art.

[0067] II. Recombinant Adenoviral Vectors

[0068] The compositions of this invention include vectors that deliver aheterologous molecule to cells, either for therapeutic or vaccinepurposes. As used herein, a vector may include any genetic elementincluding, without limitation, naked DNA, a phage, transposon, cosmid,episome, plasmid, or a virus. Such vectors contain simian adenovirus DNAof any of the serotypes described herein, (e.g., Pan5, Pan6, Pan7,baboon adenovirus ATCC-VR 275, Rhesus monkey strains, ATCC-VR 209,ATCC-VR 275, ATCC VR 353, ATCC VR 355, and African Green Monkey strainsATCC VR-541, ATCC VR 941, ATCC VR 942, and ATCC 943, SV1, SV25 and/orSV39) and a minigene. By “minigene” is meant the combination of aselected heterologous gene and the other regulatory elements necessaryto drive translation, transcription and/or expression of the geneproduct in a host cell.

[0069] Typically, an adenoviral vector of the invention is designed suchthat the minigene is located in a nucleic acid molecule that containsother adenoviral sequences in the region native to a selected adenoviralgene. The minigene may be inserted into an existing gene region todisrupt the function of that region, if desired. Alternatively, theminigene may be inserted into the site of a partially or fully deletedadenoviral gene. For example, the minigene may be located in the site ofsuch as the site of a functional E1 deletion or functional E3 deletion,among others that may be selected. The term “functionally deleted” or“functional deletion” means that a sufficient amount of the gene regionis removed or otherwise damaged, e.g., by mutation or modification, sothat the gene region is no longer capable of producing functionalproducts of gene expression. If desired, the entire gene region may beremoved. Other suitable sites for gene disruption or deletion arediscussed elsewhere in the application.

[0070] For example, for a production vector useful for generation of arecombinant virus, the vector may contain the minigene and either the 5′end of the adenoviral genome or the 3′ end of the adenoviral genome, orboth the 5′ and 3′ ends of the adenoviral genome. The 5′ end of theadenoviral genome contains the 5′ cis-elements necessary for packagingand replication; i.e., the 5′ inverted terminal repeat (ITR) sequences(which functions as origins of replication) and the native 5′ packagingenhancer domains (that contain sequences necessary for packaging linearAd genomes and enhancer elements for the E1 promoter). The 3′ end of theadenoviral genome includes the 3′ cis-elements (including the ITRS)necessary for packaging and encapsidation. Suitably, a recombinantadenovirus contains both 5′ and 3′ adenoviral cis-elements and theminigene is located between the 5′ and 3′ adenoviral sequences. Anyadenoviral vector of the invention may also contain additionaladenoviral sequences.

[0071] Suitably, these adenoviral vectors of the invention contain oneor more adenoviral elements derived from an adenoviral genome of theinvention. In one embodiment, the vectors contain adenoviral ITRs fromPan5, Pan6, Pan7, SV1, SV25 or SV39 and additional adenoviral sequencesfrom the same adenoviral serotype. In another embodiment, the vectorscontain adenoviral sequences that are derived from a differentadenoviral serotype than that which provides the ITRs. As definedherein, a pseudotyped adenovirus refers to an adenovirus in which thecapsid protein of the adenovirus is from a different serotype than theserotype which provides the ITRs. The selection of the serotype of theITRs and the serotype of any other adenoviral sequences present invector is not a limitation of the present invention. A variety ofadenovirus strains are available from the American Type CultureCollection, Manassas, Va., or available by request from a variety ofcommercial and institutional sources. Further, the sequences of manysuch strains are available from a variety of databases including, e.g.,PubMed and GenBank. Homologous adenovirus vectors prepared from othersimian or from human adenoviruses are described in the publishedliterature [see, for example, U.S. Pat. No. 5,240,846]. The DNAsequences of a number of adenovirus types are available from GenBank,including type AdS [GenBank Accession No. M73260]. The adenovirussequences may be obtained from any known adenovirus serotype, such asserotypes 2, 3, 4, 7, 12 and 40, and further including any of thepresently identified human types. Similarly adenoviruses known to infectnon-human animals (e.g., simians) may also be employed in the vectorconstructs of this invention. See, e.g., U.S. Pat. No. 6,083,716.

[0072] The viral sequences, helper viruses, if needed, and recombinantviral particles, and other vector components and sequences employed inthe construction of the vectors described herein are obtained asdescribed above. The DNA sequences of the simian adenovirus sequences ofthe invention are employed to construct vectors and cell lines useful inthe preparation of such vectors.

[0073] Modifications of the nucleic acid sequences forming the vectorsof this invention, including sequence deletions, insertions, and othermutations may be generated using standard molecular biologicaltechniques and are within the scope of this invention.

[0074] A. The “Minigene”

[0075] The methods employed for the selection of the transgene, thecloning and construction of the “minigene” and its insertion into theviral vector are within the skill in the art given the teachingsprovided herein.

[0076] 1. The Transgene

[0077] The transgene is a nucleic acid sequence, heterologous to thevector sequences flanking the transgene, which encodes a polypeptide,protein, or other product, of interest. The nucleic acid coding sequenceis operatively linked to regulatory components in a manner which permitstransgene transcription, translation, and/or expression in a host cell.

[0078] The composition of the transgene sequence will depend upon theuse to which the resulting vector will be put. For example, one type oftransgene sequence includes a reporter sequence, which upon expressionproduces a detectable signal. Such reporter sequences include, withoutlimitation, DNA sequences encoding 13-lactamase, β-galactosidase (LacZ),alkaline phosphatase, thymidine kinase, green fluorescent protein (GFP),chloramphenicol acetyltransferase (CAT), luciferase, membrane boundproteins including, for example, CD2, CD4, CD8, the influenzahemagglutinin protein, and others well known in the art, to which highaffinity antibodies directed thereto exist or can be produced byconventional means, and fusion proteins comprising a membrane boundprotein appropriately fused to an antigen tag domain from, among others,hemagglutinin or Myc. These coding sequences, when associated withregulatory elements which drive their expression, provide signalsdetectable by conventional means, including enzymatic, radiographic,calorimetric, fluorescence or other spectrographic assays, fluorescentactivating cell sorting assays and immunological assays, includingenzyme linked immunosorbent assay (ELISA), radioimmunoassay (RIA) andimmunohistochemistry. For example, where the marker sequence is the LacZgene, the presence of the vector carrying the signal is detected byassays for beta-galactosidase activity. Where the transgene is GFP orluciferase, the vector carrying the signal may be measured visually bycolor or light production in a luminometer.

[0079] However, desirably, the transgene is a non-marker sequenceencoding a product which is useful in biology and medicine, such asproteins, peptides, RNA, enzymes, or catalytic RNAs. Desirable RNAmolecules include tRNA, dsRNA, ribosomal RNA, catalytic RNAs, andantisense RNAs. One example of a useful RNA sequence is a sequence whichextinguishes expression of a targeted nucleic acid sequence in thetreated animal.

[0080] The transgene may be used for treatment, e.g., of geneticdeficiencies, as a cancer therapeutic or vaccine, for induction of animmune response, and/or for prophylactic vaccine purposes. As usedherein, induction of an immune response refers to the ability of amolecule (e.g., a gene product) to induce a T cell and/or a humoralimmune response to the molecule. The invention further includes usingmultiple transgenes, e.g., to correct or ameliorate a condition causedby a multi-subunit protein. In certain situations, a different transgenemay be used to encode each subunit of a protein, or to encode differentpeptides or proteins. This is desirable when the size of the DNAencoding the protein subunit is large, e.g., for an immunoglobulin, theplatelet-derived growth factor, or a dystrophin protein. In order forthe cell to produce the multi-subunit protein, a cell is infected withthe recombinant virus containing each of the different subunits.Alternatively, different subunits of a protein may be encoded by thesame transgene. In this case, a single transgene includes the DNAencoding each of the subunits, with the DNA for each subunit separatedby an internal ribozyme entry site (IRES). This is desirable when thesize of the DNA encoding each of the subunits is small, e.g., the totalsize of the DNA encoding the subunits and the IRES is less than fivekilobases. As an alternative to an IRES, the DNA may be separated bysequences encoding a 2A peptide, which self-cleaves in apost-translational event. See, e.g., M. L. Donnelly, etal, J. Gen.Virol., 78(Pt 1):13-21 (January 1997); Furler, S., etal, Gene Ther.,8(11):864-873 (June 2001); Klump H., et al., Gene Ther., 8(10):811-817(May 2001). This 2A peptide is significantly smaller than an IRES,making it well suited for use when space is a limiting factor. However,the selected transgene may encode any biologically active product orother product, e.g., a product desirable for study.

[0081] Suitable transgenes may be readily selected by one of skill inthe art. The selection of the transgene is not considered to be alimitation of this invention.

[0082] 2. Regulatory Elements

[0083] In addition to the major elements identified above for theminigene, the vector also includes conventional control elementsnecessary which are operably linked to the transgene in a manner thatpermits its transcription, translation and/or expression in a celltransfected with the plasmid vector or infected with the virus producedby the invention. As used herein, “operably linked” sequences includeboth expression control sequences that are contiguous with the gene ofinterest and expression control sequences that act in trans or at adistance to control the gene of interest.

[0084] Expression control sequences include appropriate transcriptioninitiation, termination, promoter and enhancer sequences; efficient RNAprocessing signals such as splicing and polyadenylation (polyA) signals;sequences that stabilize cytoplasmic mRNA; sequences that enhancetranslation efficiency (i.e., Kozak consensus sequence); sequences thatenhance protein stability; and when desired, sequences that enhancesecretion of the encoded product. A great number of expression controlsequences, including promoters which are native, constitutive, inducibleand/or tissue-specific, are known in the art and may be utilized.

[0085] Examples of constitutive promoters include, without limitation,the retroviral Rous sarcoma virus (RSV) LTR promoter (optionally withthe RSV enhancer), the cytomegalovirus (CMV) promoter (optionally withthe CMV enhancer) [see, e.g., Boshart et al, Cell, 41:521-530 (1985)],the SV40 promoter, the dihydrofolate reductase promoter, the β-actinpromoter, the phosphoglycerol kinase (PGK) promoter, and the EF1apromoter [Invitrogen].

[0086] Inducible promoters allow regulation of gene expression and canbe regulated by exogenously supplied compounds, environmental factorssuch as temperature, or the presence of a specific physiological state,e.g., acute phase, a particular differentiation state of the cell, or inreplicating cells only. Inducible promoters and inducible systems areavailable from a variety of commercial sources, including, withoutlimitation, Invitrogen, Clontech and Ariad. Many other systems have beendescribed and can be readily selected by one of skill in the art. Forexample, inducible promoters include the zinc-inducible sheepmetallothionine (MT) promoter and the dexamethasone (Dex)-induciblemouse mammary tumor virus (MMTV) promoter. Other inducible systemsinclude the T7 polymerase promoter system [WO 98/10088]; the ecdysoneinsect promoter [No et al, Proc. Natl. Acad. Sci. USA, 93:3346-3351(1996)], the tetracycline-repressible system [Gossen et al, Proc. Natl.Acad. Sci. USA, 89:5547-5551 (1992)], the tetracycline-inducible system[Gossen et al, Science, 268:1766-1769 (1995), see also Harvey et al,Curr. Opin. Chem. Biol., 2:512-518 (1998)]. Other systems include theFK506 dimer, VP16 or p65 using castradiol, diphenol murislerone, theRU486-inducible system [Wang et al, Nat. Biotech., 15:239-243 (1997) andWang et al, Gene Ther., 4:432-441 (1997)] and the rapamycin-induciblesystem [Magari et al, J. Clin. Invest., 100:2865-2872 (1997)]. Theeffectiveness of some inducible promoters increases over time. In suchcases one can enhance the effectiveness of such systems by insertingmultiple repressors in tandem, e.g., TetR linked to a TetR by an IRES.Alternatively, one can wait at least 3 days before screening for thedesired function. One can enhance expression of desired proteins byknown means to enhance the effectiveness of this system. For example,using the Woodchuck Hepatitis Virus Posttranscriptional RegulatoryElement (WPRE).

[0087] In another embodiment, the native promoter for the transgene willbe used. The native promoter may be preferred when it is desired thatexpression of the transgene should mimic the native expression. Thenative promoter may be used when expression of the transgene must beregulated temporally or developmentally, or in a tissue-specific manner,or in response to specific transcriptional stimuli. In a furtherembodiment, other native expression control elements, such as enhancerelements, polyadenylation sites or Kozak consensus sequences may also beused to mimic the native expression.

[0088] Another embodiment of the transgene includes a transgene operablylinked to a tissue-specific promoter. For instance, if expression inskeletal muscle is desired, a promoter active in muscle should be used.These include the promoters from genes encoding skeletal β-actin, myosinlight chain 2A, dystrophin, muscle creatine kinase, as well as syntheticmuscle promoters with activities higher than naturally occurringpromoters (see Li et al., Nat. Biotech., 17:241-245 (1999)). Examples ofpromoters that are tissue-specific are known for liver (albumin,Miyatake et al., J. Virol., 71:5124-32 (1997); hepatitis B virus corepromoter, Sandig et al., Gene Ther., 3:1002-9 (1996); alpha-fetoprotein(AFP), Arbuthnot et al., Hum. Gene Ther., 7:1503-14 (1996)), boneosteocalcin (Stein et al., Mol. Biol. Rep., 24:185-96 (1997)); bonesialoprotein (Chen et al., J. Bone Miner. Res., 11:654-64 (1996)),lymphocytes (CD2, Hansal et al., J. Immunol., 161:1063-8 (1998);immunoglobulin heavy chain; T cell receptor chain), neuronal such asneuron-specific enolase (NSE) promoter (Andersen et al., Cell. Mol.Neurobiol., 13:503-15 (1993)), neurofilament light-chain gene (Piccioliet al., Proc. Natl. Acad. Sci. USA, 88:5611-5 (1991)), and theneuron-specific vgf gene (Piccioli et al., Neuron, 15:373-84 (1995)),among others.

[0089] Optionally, vectors carrying transgenes encoding therapeuticallyuseful or immunogenic products may also include selectable markers orreporter genes may include sequences encoding geneticin, hygromicin orpurimycin resistance, among others. Such selectable reporters or markergenes (preferably located outside the viral genome to be packaged into aviral particle) can be used to signal the presence of the plasmids inbacterial cells, such as ampicillin resistance. Other components of thevector may include an origin of replication. Selection of these andother promoters and vector elements are conventional and many suchsequences are available [see, e.g., Sambrook et al, and references citedtherein].

[0090] These vectors are generated using the techniques and sequencesprovided herein, in conjunction with techniques known to those of skillin the art. Such techniques include conventional cloning techniques ofcDNA such as those described in texts [Sambrook et al, MolecularCloning: A Laboratory Manual, Cold Spring Harbor Press, Cold SpringHarbor, N.Y.], use of overlapping oligonucleotide sequences of theadenovirus genomes, polymerase chain reaction, and any suitable methodwhich provides the desired nucleotide sequence.

[0091] III. Production of the Recombinant Viral Particle

[0092] In one embodiment, the simian adenoviral plasmids (or othervectors) are used to produce recombinant adenoviral particles. At aminimum, a recombinant simian adenovirus (i.e., a viral particle) usefulin the invention contains the simian adenovirus cis-elements necessaryfor replication and virion encapsidation, which cis-elements flank theheterologous gene. That is, the vector contains the cis-acting 5′inverted terminal repeat (ITR) sequences of the adenoviruses whichfunction as origins of replication), the native 5′ packaging/enhancerdomains (that contain sequences necessary for packaging linear Adgenomes and enhancer elements for the E1 promoter), the heterologousmolecule, and the 5′ ITR sequences. See, for example, the techniquesdescribed for preparation of a “minimal” human Ad vector in U.S. Pat.No. 6,203,975, which is incorporated by reference, can be readilyadapted for the recombinant simian adenovirus. Optionally, therecombinant simian adenoviruses useful in this invention contain morethan the minimal simian adenovirus sequences defined above

[0093] In one embodiment, the recombinant adenoviruses are functionallydeleted in the E1a or E1b genes, and optionally bearing other mutations,e.g., temperature-sensitive mutations or deletions in other genes. Inother embodiments, it is desirable to retain an intact E1a and/or E1bregion in the recombinant adenoviruses. Such an intact E1 region may belocated in its native location in the adenoviral genome or placed in thesite of a deletion in the native adenoviral genome (e.g., in the E3region).

[0094] In the construction of useful simian adenovirus vectors fordelivery of a gene to the human (or other mammalian) cell, a range ofadenovirus nucleic acid sequences can be employed in the vectors. Forexample, all or a portion of the adenovirus delayed early gene E3 may beeliminated from the simian adenovirus sequence which forms a part of therecombinant virus. The function of simian E3 is believed to beirrelevant to the function and production of the recombinant virusparticle. Simian adenovirus vectors may also be constructed having adeletion of at least the ORF6 region of the E4 gene, and more desirablybecause of the redundancy in the function of this region, the entire E4region. Still another vector of this invention contains a deletion inthe delayed early gene E2a. Deletions may also be made in any of thelate genes L1 through L5 of the simian adenovirus genome. Similarly,deletions in the intermediate genes IX and IVa₂ may be useful for somepurposes. Other deletions may be made in the other structural ornon-structural adenovirus genes. The above discussed deletions may beused individually, i.e., an adenovirus sequence for use in the presentinvention may contain deletions in only a single region. Alternatively,deletions of entire genes or portions thereof effective to destroy theirbiological activity may be used in any combination. For example, in oneexemplary vector, the adenovirus sequence may have deletions of the E1genes and the E4 gene, or of the E1, E2a and E3 genes, or of the E1 andE3 genes, or of E1, E2a and E4 genes, with or without deletion of E3,and so on. As discussed above, such deletions may be used in combinationwith other mutations, such as temperature-sensitive mutations, toachieve a desired result.

[0095] An adenoviral vector lacking any essential adenoviral sequences(e.g., E1a, E1b, E2a, E2b, E4 ORF6, L1, L2, L3, L4 and L5) may becultured in the presence of the missing adenoviral gene products whichare required for viral infectivity and propagation of an adenoviralparticle. These helper functions may be provided by culturing theadenoviral vector in the presence of one or more helper constructs(e.g., a plasmid or virus) or a packaging host cell. See, for example,the techniques described for preparation of a “minimal” human Ad vectorin International Patent Application W096/13597, published May 9, 1996,and incorporated herein by reference.

[0096] Regardless of whether the recombinant simian adenovirus containsonly the minimal Ad sequences, or the entire Ad genome with onlyfunctional deletions in the E1 and/or E3 regions, in one embodiment, therecombinant virus contains a capsid derived from a simian adenovirus.Alternatively, in other embodiments, recombinant pseudotypedadenoviruses may be used in the methods of the invention. Suchpseudotyped adenoviruses utilize simian adenovirus capsid proteins inwhich a nucleic acid molecule carrying heterologous simian adenovirussequences, or non-simian adenovirus sequences have been packaged. Theserecombinant simian adenoviruses of the invention may be produced usingmethods that are known to those of skill in the art.

[0097] 1. Helper Viruses

[0098] Thus, depending upon the simian adenovirus gene content of theviral vectors employed to carry the minigene, a helper adenovirus ornon-replicating virus fragment may be necessary to provide sufficientsimian adenovirus gene sequences necessary to produce an infectiverecombinant viral particle containing the minigene. Useful helperviruses contain selected adenovirus gene sequences not present in theadenovirus vector construct and/or not expressed by the packaging cellline in which the vector is transfected. In one embodiment, the helpervirus is replication-defective and contains a variety of adenovirusgenes in addition to the sequences described above. Such a helper virusis desirably used in combination with an E1-expressing cell line.

[0099] Helper viruses may also be formed into poly-cation conjugates asdescribed in Wu et al, J. Biol. Chem., 264:16985-16987 (1989); K. J.Fisher and J. M. Wilson, Biochem. J, 299:49 (Apr. 1, 1994). Helper virusmay optionally contain a second reporter minigene. A number of suchreporter genes are known to the art. The presence of a reporter gene onthe helper virus which is different from the transgene on the adenovirusvector allows both the Ad vector and the helper virus to beindependently monitored. This second reporter is used to enableseparation between the resulting recombinant virus and the helper virusupon purification.

[0100] 2. Complementation Cell Lines

[0101] To generate recombinant simian adenoviruses (Ad) deleted in anyof the genes described above, the function of the deleted gene region,if essential to the replication and infectivity of the virus, must besupplied to the recombinant virus by a helper virus or cell line, i.e.,a complementation or packaging cell line. In many circumstances, a cellline expressing the human E1 can be used to transcomplement the chimp Advector. This is particularly advantageous because, due to the diversitybetween the chimp Ad sequences of the invention and the human AdE1sequences found in currently available packaging cells, the use of thecurrent human E1-containing cells prevents the generation ofreplication-competent adenoviruses during the replication and productionprocess. However, in certain circumstances, it will be desirable toutilize a cell line which expresses the E1 gene products can be utilizedfor production of an E1-deleted simian adenovirus. Such cell lines havebeen described. See, e.g., U.S. Pat. No. 6,083,716.

[0102] If desired, one may utilize the sequences provided herein togenerate a packaging cell or cell line that expresses, at a minimum, theadenovirus E1 gene from Pan5, Pan6, Pan7, SV1, SV25 or SV39 under thetranscriptional control of a promoter for expression in a selectedparent cell line. Inducible or constitutive promoters may be employedfor this purpose. Examples of such promoters are described in detailelsewhere in this specification. A parent cell is selected for thegeneration of a novel cell line expressing any desired AdPan5, Pan6,Pan7, SV1, SV25 or SV39 gene. Without limitation, such a parent cellline may be HeLa [ATCC Accession No. CCL 2], A549 [ATCC Accession No.CCL 185], HEK 293, KB [CCL 17], Detroit [e.g., Detroit 510, CCL 72] andWI-38 [CCL 75] cells, among others. These cell lines are all availablefrom the American Type Culture Collection, 10801 University Boulevard,Manassas, Va. 20110-2209. Other suitable parent cell lines may beobtained from other sources.

[0103] Such E1-expressing cell lines are useful in the generation ofrecombinant simian adenovirus E1 deleted vectors. Additionally, oralternatively, the invention provides cell lines that express one ormore simian adenoviral gene products, e.g., E1a, E1b, E2a, and/or E4ORF6, can be constructed using essentially the same procedures for usein the generation of recombinant simian viral vectors. Such cell linescan be utilized to transcomplement adenovirus vectors deleted in theessential genes that encode those products, or to provide helperfunctions necessary for packaging of a helper-dependent virus (e.g.,adeno-associated virus). The preparation of a host cell according tothis invention involves techniques such as assembly of selected DNAsequences. This assembly may be accomplished utilizing conventionaltechniques. Such techniques include cDNA and genomic cloning, which arewell known and are described in Sambrook et al., cited above, use ofoverlapping oligonucleotide sequences of the adenovirus genomes,combined with polymerase chain reaction, synthetic methods, and anyother suitable methods which provide the desired nucleotide sequence.

[0104] In still another alternative, the essential adenoviral geneproducts are provided in trans by the adenoviral vector and/or helpervirus. In such an instance, a suitable host cell can be selected fromany biological organism, including prokaryotic (e.g., bacterial) cells,and eukaryotic cells, including, insect cells, yeast cells and mammaliancells. Particularly desirable host cells are selected from among anymammalian species, including, without limitation, cells such as A549,WEHI, 3T3, 10T1/2, HEK 293 cells or PERC6 (both of which expressfunctional adenoviral E1) [Fallaux, F J et al, (1998), Hum Gene Ther,9:1909-1917], Saos, C2C12, L cells, HT1080, HepG2 and primaryfibroblast, hepatocyte and myoblast cells derived from mammals includinghuman, monkey, mouse, rat, rabbit, and hamster. The selection of themammalian species providing the cells is not a limitation of thisinvention; nor is the type of mammalian cell, i.e., fibroblast,hepatocyte, tumor cell, etc.

[0105] 3. Assembly of Viral Particle and Transfection of a Cell Line

[0106] Generally, when delivering the vector comprising the minigene bytransfection, the vector is delivered in an amount from about 5 μg toabout 100 μg DNA, and preferably about 10 to about 50 μg DNA to about1×10⁴ cells to about 1×10¹³ cells, and preferably about 10⁵ cells.However, the relative amounts of vector DNA to host cells may beadjusted, taking into consideration such factors as the selected vector,the delivery method and the host cells selected.

[0107] The vector may be any vector known in the art or disclosed above,including naked DNA, a plasmid, phage, transposon, cosmids, episomes,viruses, etc. Introduction into the host cell of the vector may beachieved by any means known in the art or as disclosed above, includingtransfection, and infection. One or more of the adenoviral genes may bestably integrated into the genome of the host cell, stably expressed asepisomes, or expressed transiently. The gene products may all beexpressed transiently, on an episome or stably integrated, or some ofthe gene products may be expressed stably while others are expressedtransiently. Furthermore, the promoters for each of the adenoviral genesmay be selected independently from a constitutive promoter, an induciblepromoter or a native adenoviral promoter. The promoters may be regulatedby a specific physiological state of the organism or cell (i.e., by thedifferentiation state or in replicating or quiescent cells) or byexogenously-added factors, for example.

[0108] Introduction of the molecules (as plasmids or viruses) into thehost cell may also be accomplished using techniques known to the skilledartisan and as discussed throughout the specification. In preferredembodiment, standard transfection techniques are used, e.g., CaPO₄transfection or electroporation.

[0109] Assembly of the selected DNA sequences of the adenovirus (as wellas the transgene and other vector elements into various intermediateplasmids, and the use of the plasmids and vectors to produce arecombinant viral particle are all achieved using conventionaltechniques. Such techniques include conventional cloning techniques ofcDNA such as those described in texts [Sambrook et al, cited above], useof overlapping oligonucleotide sequences of the adenovirus genomes,polymerase chain reaction, and any suitable method which provides thedesired nucleotide sequence. Standard transfection and co-transfectiontechniques are employed, e.g., CaPO₄ precipitation techniques. Otherconventional methods employed include homologous recombination of theviral genomes, plaquing of viruses in agar overlay, methods of measuringsignal generation, and the like.

[0110] For example, following the construction and assembly of thedesired minigene-containing viral vector, the vector is transfected invitro in the presence of a helper virus into the packaging cell line.Homologous recombination occurs between the helper and the vectorsequences, which permits the adenovirus-transgene sequences in thevector to be replicated and packaged into virion capsids, resulting inthe recombinant viral vector particles. The current method for producingsuch virus particles is transfection-based. However, the invention isnot limited to such methods.

[0111] The resulting recombinant simian adenoviruses are useful intransferring a selected transgene to a selected cell. In in vivoexperiments with the recombinant virus grown in the packaging celllines, the E1-deleted recombinant simian adenoviral vectors of theinvention demonstrate utility in transferring a transgene to anon-simian, preferably a human, cell.

[0112] IV. Use of the Recombinant Adenovirus Vectors

[0113] The recombinant simian adenovirus vectors of the invention areuseful for gene transfer to a human or non-simian veterinary patient invitro, ex vivo, and in vivo.

[0114] The recombinant adenovirus vectors described herein can be usedas expression vectors for the production of the products encoded by theheterologous genes in vitro. For example, the recombinant adenovirusescontaining a gene inserted into the location of an E1 deletion may betransfected into an E1-expressing cell line as described above.Alternatively, replication-competent adenoviruses may be used in anotherselected cell line. The transfected cells are then cultured in theconventional manner, allowing the recombinant adenovirus to express thegene product from the promoter. The gene product may then be recoveredfrom the culture medium by known conventional methods of proteinisolation and recovery from culture.

[0115] A Pan5, Pan6, Pan7, SV1, SV25 or SV39-derived recombinant simianadenoviral vector of the invention provides an efficient gene transfervehicle that can deliver a selected transgene to a selected host cell invivo or ex vivo even where the organism has neutralizing antibodies toone or more AAV serotypes. In one embodiment, the rAAV and the cells aremixed ex vivo; the infected cells are cultured using conventionalmethodologies; and the transduced cells are re-infused into the patient.These compositions are particularly well suited to gene delivery fortherapeutic purposes and for immunization, including inducing protectiveimmunity.

[0116] More commonly, the Pan 5, Pan6, Pan7, SV1, SV25, or SV39recombinant adenoviral vectors of the invention will be utilized fordelivery of therapeutic or immunogenic molecules, as described below. Itwill be readily understood for both applications, that the recombinantadenoviral vectors of the invention are particularly well suited for usein regimens involving repeat delivery of recombinant adenoviral vectors.Such regimens typically involve delivery of a series of viral vectors inwhich the viral capsids are alternated. The viral capsids may be changedfor each subsequent administration, or after a pre-selected number ofadministrations of a particular serotype capsid (e.g., one, two, three,four or more). Thus, a regimen may involve delivery of a rAd with afirst simian capsid, delivery with a rAd with a second simian capsid,and delivery with a third simian capsid. A variety of other regimenswhich use the Ad capsids of the invention alone, in combination with oneanother, or in combination with other Ad serotypes will be apparent tothose of skill in the art. Optionally, such a regimen may involveadministration of rAd with capsids of other non-human primateadenoviruses, human adenoviruses, or artificial serotypes such as aredescribed herein. Each phase of the regimen may involve administrationof a series of injections (or other delivery routes) with a single Adserotype capsid followed by a series with another Ad serotype capsid.Alternatively, the recombinant Ad vectors of the invention may beutilized in regimens involving other non-adenoviral-mediated deliverysystems, including other viral systems, non-viral delivery systems,protein, peptides, and other biologically active molecules.

[0117] The following sections will focus on exemplary molecules whichmay be delivered via the adenoviral vectors of the invention.

[0118] 5 A. Ad-Mediated Delivery of Therapeutic Molecules

[0119] In one embodiment, the above-described recombinant vectors areadministered to humans according to published methods for gene therapy.A simian viral vector bearing the selected transgene may be administeredto a patient, preferably suspended in a biologically compatible solutionor pharmaceutically acceptable delivery vehicle. A suitable vehicleincludes sterile saline that may be formatted with a variety ofbuffering solutions (e.g., phosphate buffered saline). Other aqueous andnon-aqueous isotonic sterile injection solutions and aqueous andnon-aqueous sterile suspensions known to be pharmaceutically acceptablecarriers and well known to those of skill in the art may be employed forthis purpose. Other exemplary carriers include sterile saline, lactose,sucrose, calcium phosphate, gelatin, dextran, agar, pectin, peanut oil,sesame oil, and water. The selection of the carrier is not a limitationof the present invention.

[0120] The simian adenoviral vectors are administered in sufficientamounts to transduce the target cells and to provide sufficient levelsof gene transfer and expression to provide a therapeutic benefit withoutundue adverse or with medically acceptable physiological effects, whichcan be determined by those skilled in the medical arts. Conventional andpharmaceutically acceptable routes of administration include, but arenot limited to, direct delivery to the retina and other intraoculardelivery methods, direct delivery to the liver, inhalation, intranasal,intravenous, intramuscular, intratracheal, subcutaneous, intradermal,rectal, oral and other parenteral routes of administration. Routes ofadministration may be combined, if desired, or adjusted depending uponthe transgene or the condition. The route of administration primarilywill depend on the nature of the condition being treated.

[0121] Dosages of the viral vector will depend primarily on factors suchas the condition being treated, the age, weight and health of thepatient, and may thus vary among patients. For example, atherapeutically effective adult human or veterinary dosage of the viralvector is generally in the range of from about 100 μL to about 100 mL ofa carrier containing concentrations of from about 1×10⁶ to about 1×10¹⁵particles, about 1×10¹⁵ to 1×10 ¹³ particles, or about 1×10⁹ to 1×10¹²particles virus. Dosages will range depending upon the size of theanimal and the route of administration. For example, a suitable human orveterinary dosage (for about an 80 kg animal) for intramuscularinjection is in the range of about 1×10⁹ to about 5×10¹² particles permL, for a single site. Optionally, multiple sites of administration maybe delivered. In another example, a suitable human or veterinary dosagemay be in the range of about 1×10¹¹ to about 10×10 ¹⁵ particles for anoral formulation. One of skill in the art may adjust these doses,depending the route of administration, and the therapeutic or vaccinalapplication for which the recombinant vector is employed. The levels ofexpression of the transgene, or for an immunogen, the level ofcirculating antibody, can be monitored to determine the frequency ofdosage administration. Yet other methods for determining the timing offrequency of administration will be readily apparent to one of skill inthe art.

[0122] An optional method step involves the co-administration to thepatient, either concurrently with, or before or after administration ofthe viral vector, of a suitable amount of a short acting immunemodulator. The selected immune modulator is defined herein as an agentcapable of inhibiting the formation of neutralizing antibodies directedagainst the recombinant vector of this invention or capable ofinhibiting cytolytic T lymphocyte (CTL) elimination of the vector. Theimmune modulator may interfere with the interactions between the Thelper subsets (T_(H1) or T_(H2)) and B cells to inhibit neutralizingantibody formation. Alternatively, the immune modulator may inhibit theinteraction between TH₁ cells and CTLs to reduce the occurrence of CTLelimination of the vector. A variety of useful immune modulators anddosages for use of same are disclosed, for example, in Yang et al., J.Virol., 70(9) (September 1996); International Patent Application No.WO96/12406, published May 2, 1996; and International Patent ApplicationNo.PCT/US96/03035, all incorporated herein by reference.

[0123] 1. Therapeutic Transgenes

[0124] Useful therapeutic products encoded by the transgene includehormones and growth and differentiation factors including, withoutlimitation, insulin, glucagon, growth hormone (GH), parathyroid hormone(PTH), growth hormone releasing factor (GRF), follicle stimulatinghormone (FSH), luteinizing hormone (LH), human chorionic gonadotropin(hCG), vascular endothelial growth factor (VEGF), angiopoietins,angiostatin, granulocyte colony stimulating factor (GCSF),erythropoietin (EPO), connective tissue growth factor (CTGF), basicfibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF),epidermal growth factor (EGF), transforming growth factor (TGF ),platelet-derived growth factor (PDGF), insulin growth factors I and II(IGF-I and IGF-II), any one of the transforming growth factorsuperfamily, including TGF, activins, inhibins, or any of the bonemorphogenic proteins (BMP) BMPs 1-15, any one of theheregluin/neuregulin/ARIA/neu differentiation factor (NDF) family ofgrowth factors, nerve growth factor (NGF), brain-derived neurotrophicfactor (BDNF), neurotrophins NT-3 and NT-4/5, ciliary neurotrophicfactor (CNTF), glial cell line derived neurotrophic factor (GDNF),neurturin, agrin, any one of the family of semaphorins/collapsins,netrin-1 and netrin-2, hepatocyte growth factor (HGF), ephrins, noggin,sonic hedgehog and tyrosine hydroxylase.

[0125] Other useful transgene products include proteins that regulatethe immune system including, without limitation, cytokines andlymphokines such as thrombopoietin (TPO), interleukins (IL) IL-1 throughIL-25 (including, e.g., IL-2, IL-4, IL-12 and IL-1 8), monocytechemoattractant protein, leukemia inhibitory factor,granulocyte-macrophage colony stimulating factor, Fas ligand, tumornecrosis factors and, interferons, and, stem cell factor, flk-2/flt3ligand. Gene products produced by the immune system are also useful inthe invention. These include, without limitation, immunoglobulins IgG,IgM, IgA, IgD and IgE, chimeric immunoglobulins, humanized antibodies,single chain antibodies, T cell receptors, chimeric T cell receptors,single chain T cell receptors, class I and class II MHC molecules, aswell as engineered immunoglobulins and MHC molecules. Useful geneproducts also include complement regulatory proteins such as complementregulatory proteins, membrane cofactor protein (MCP), decay acceleratingfactor (DAF), CR1, CF2 and CD59.

[0126] Still other useful gene products include any one of the receptorsfor the hormones, growth factors, cytokines, lymphokines, regulatoryproteins and immune system proteins. The invention encompasses receptorsfor cholesterol regulation, including the low density lipoprotein (LDL)receptor, high density lipoprotein (HDL) receptor, the very low densitylipoprotein (VLDL) receptor, and the scavenger receptor. The inventionalso encompasses gene products such as members of the steroid hormonereceptor superfamily including glucocorticoid receptors and estrogenreceptors, Vitamin D receptors and other nuclear receptors. In addition,useful gene products include transcription factors such as jun, fos,max, mad, serum response factor (SRF), AP-1, AP2, myb, MyoD andmyogenin, ETS-box containing proteins, TFE3, E2F, ATF1, ATF2, ATF3,ATF4, ZF5, NFAT, CREB, HNF-4, C/EBP, SPI, CCAAT-box binding proteins,interferon regulation factor (IRF-1), Wilms tumor protein, ETS-bindingprotein, STAT, GATA-box binding proteins, e.g., GATA-3, and the forkheadfamily of winged helix proteins.

[0127] Other useful gene products include, carbamoyl synthetase 1,ornithine transcarbamylase, arginosuccinate synthetase, arginosuccinatelyase, arginase, fumarylacetacetate hydrolase, phenylalaninehydroxylase, alpha-1 antitrypsin, glucose-6-phosphatase, porphobilinogendeaminase, factor VIII, factor IX, cystathione beta-synthase, branchedchain ketoacid decarboxylase, albumin, isovaleryl-coA dehydrogenase,propionyl CoA carboxylase, methyl malonyl CoA mutase, glutaryl CoAdehydrogenase, insulin, beta-glucosidase, pyruvate carboxylate, hepaticphosphorylase, phosphorylase kinase, glycine decarboxylase, H-protein,T-protein, a cystic fibrosis transmembrane regulator (CFTR) sequence,and a dystrophin cDNA sequence.

[0128] Other useful gene products include non-naturally occurringpolypeptides, such as chimeric or hybrid polypeptides having anon-naturally occurring amino acid sequence containing insertions,deletions or amino acid substitutions. For example, single-chainengineered immunoglobulins could be useful in certain immunocompromisedpatients. Other types of non-naturally occurring gene sequences includeantisense molecules and catalytic nucleic acids, such as ribozymes,which could be used to reduce overexpression of a target.

[0129] Reduction and/or modulation of expression of a gene areparticularly desirable for treatment of hyperproliferative conditionscharacterized by hyperproliferating cells, as are cancers and psoriasis.Target polypeptides include those polypeptides which are producedexclusively or at higher levels in hyperproliferative cells as comparedto normal cells. Target antigens include polypeptides encoded byoncogenes such as myb, myc, fyn, and the translocation gene bcr/abl,ras, src, P53, neu, trk and EGRF. In addition to oncogene products astarget antigens, target polypeptides for anti-cancer treatments andprotective regimens include variable regions of antibodies made by Bcell lymphomas and variable regions of T cell receptors of T celllymphomas which, in some embodiments, are also used as target antigensfor autoimmune disease. Other tumor-associated polypeptides can be usedas target polypeptides such as polypeptides which are found at higherlevels in tumor cells including the polypeptide recognized by monoclonalantibody 17-1A and folate binding polypeptides.

[0130] Other suitable therapeutic polypeptides and proteins includethose which may be useful for treating individuals suffering fromautoimmune diseases and disorders by conferring a broad based protectiveimmune response against targets that are associated with autoimmunityincluding cell receptors and cells which produce self-directedantibodies. T cell mediated autoimmune diseases include Rheumatoidarthritis (RA), multiple sclerosis (MS), Sjogren's syndrome,sarcoidosis, insulin dependent diabetes mellitus (IDDM), autoimmunethyroiditis, reactive arthritis, ankylosing spondylitis, scleroderma,polymyositis, dermatomyositis, psoriasis, vasculitis, Wegener'sgranulomatosis, Crohn's disease and ulcerative colitis. Each of thesediseases is characterized by T cell receptors (TCRs) that bind toendogenous antigens and initiate the inflammatory cascade associatedwith autoimmune diseases.

[0131] The simian adenoviral vectors of the invention are particularlywell suited for therapeutic regimens in which multipleadenoviral-mediated deliveries of transgenes is desired, e.g., inregimens involving redelivery of the same transgene or in combinationregimens involving delivery of other transgenes. Such regimens mayinvolve administration of a Pan5, Pan6, Pan7, SV1, SV25 or SV39 simianadenoviral vector, followed by re-administration with a vector from thesame serotype adenovirus. Particularly desirable regimens involveadministration of a Pan5, Pan6, Pan7, SV1, SV25 or SV39 simianadenoviral vector of the invention, in which the serotype of the viralvector delivered in the first administration differs from the serotypeof the viral vector utilized in one or more of the subsequentadministrations. For example, a therapeutic regimen involvesadministration of a Pan5, Pan6, Pan7, SV1, SV25 or SV39 vector andrepeat administration with one or more adenoviral vectors of the same ordifferent serotypes. In another example, a therapeutic regimen involvesadministration of an adenoviral vector followed by repeat administrationwith a Pan5, Pan6, Pan7, SV1, SV25 or SV39 vector of the invention whichdiffers from the serotype of the first delivered adenoviral vector, andoptionally further administration with another vector which is the sameor, preferably, differs from the serotype of the vector in the prioradministration steps. These regimens are not limited to delivery ofadenoviral vectors constructed using the Pan5, Pan6, Pan7, SV1, SV25 orSV39 simian serotypes of the invention. Rather, these regimens canreadily utilize vectors other adenoviral serotypes, including, withoutlimitation, other simian adenoviral serotypes (e.g., Pan9 or C68, C1,etc), other non-human primate adenoviral serotypes, or human adenoviralserotypes, in combination with one or more of the Pan5, Pan6, Pan7, SV1,SV25 or SV39 vectors of the invention.

[0132] Examples of such simian, other non-human primate and humanadenoviral serotypes are discussed elsewhere in this document. Further,these therapeutic regimens may involve either simultaneous or sequentialdelivery of Pan 5, Pan6, Pan7, SV1, SV25, and/or SV39 adenoviral vectorsof the invention in combination with non-adenoviral vectors, non-viralvectors, and/or a variety of other therapeutically useful compounds ormolecules. The present invention is not limited to these therapeuticregimens, a variety of which will be readily apparent to one of skill inthe art.

[0133] B. Ad-Mediated Delivery of Immunogenic Transgenes

[0134] The recombinant simian adenoviruses may also be employed asimmunogenic compositions. As used herein, an immunogenic composition isa composition to which a humoral (e.g., antibody) or cellular (e.g., acytotoxic T cell) response is mounted to a transgene product deliveredby the immunogenic composition following delivery to a mammal, andpreferably a primate. The present invention provides a recombinantsimian Ad that can contain in any of its adenovirus sequence deletions agene encoding a desired immunogen. The simian adenovirus is likely to bebetter suited for use as a live recombinant virus vaccine in differentanimal species compared to an adenovirus of human origin, but is notlimited to such a use. The recombinant adenoviruses can be used asprophylactic or therapeutic vaccines against any pathogen for which theantigen(s) crucial for induction of an immune response and able to limitthe spread of the pathogen has been identified and for which the cDNA isavailable.

[0135] Such vaccinal (or other immunogenic) compositions are formulatedin a suitable delivery vehicle, as described above. Generally, doses forthe immunogenic compositions are in the range defined above fortherapeutic compositions. The levels of immunity of the selected genecan be monitored to determine the need, if any, for boosters. Followingan assessment of antibody titers in the serum, optional boosterimmunizations may be desired.

[0136] Optionally, a vaccinal composition of the invention may beformulated to contain other components, including, e.g. adjuvants,stabilizers, pH adjusters, preservatives and the like. Suitableexemplary preservatives include chlorobutanol, potassium sorbate, sorbicacid, sulfur dioxide, propyl gallate, the parabens, ethyl vanillin,glycerin, phenol, and parachlorophenol. Suitable chemical stabilizersinclude gelatin and albumin. Suitable exemplary adjuvants include, amongothers, immune-stimulating complexes (ISCOMS), LPS analogs including3-O-deacylated monophosphoryl lipid A (Ribi Immunochem Research, Inc.;Hamilton, Mont.), mineral oil and water, aluminum hydroxide, Amphigen,Avirdine, L121/squalene, muramyl peptides, and saponins, such as Quil A,and any biologically active factor, such as cytokine, an interleukin, achemokine, a ligands, and optimally combinations thereof. Certain ofthese biologically active factors can be expressed in vivo, e.g., via aplasmid or viral vector. For example, such an adjuvant can beadministered with a priming DNA vaccine encoding an antigen to enhancethe antigen-specific immune response compared with the immune responsegenerated upon priming with a DNA vaccine encoding the antigen only.

[0137] The recombinant adenoviruses are administered in a “animmunogenic amount”, that is, an amount of recombinant adenovirus thatis effective in a route of administration to transfect the desired cellsand provide sufficient levels of expression of the selected gene toinduce an immune response. Where protective immunity is provided, therecombinant adenoviruses are considered to be vaccine compositionsuseful in preventing infection and/or recurrent disease.

[0138] Alternatively, or in addition, the vectors of the invention maycontain a transgene encoding a peptide, polypeptide or protein whichinduces an immune response to a selected immunogen. The recombinantadenoviruses of this invention are expected to be highly efficacious atinducing cytolytic T cells and antibodies to the inserted heterologousantigenic protein expressed by the vector.

[0139] For example, immunogens may be selected from a variety of viralfamilies. Example of desirable viral families against which an immuneresponse would be desirable include, the picornavirus family, whichincludes the genera rhinoviruses, which are responsible for about 50% ofcases of the common cold; the genera enteroviruses, which includepolioviruses, coxsackieviruses, echoviruses, and human enterovirusessuch as hepatitis A virus; and the genera apthoviruses, which areresponsible for foot and mouth diseases, primarily in non-human animals.Within the picomavirus family of viruses, target antigens include theVP1, VP2, VP3, VP4, and VPG. Another viral family includes thecalcivirus family, which encompasses the Norwalk group of viruses, whichare an important causative agent of epidemic gastroenteritis. Stillanother viral family desirable for use in targeting antigens forinducing immune responses in humans and non-human animals is thetogavirus family, which includes the genera alphavirus, which includeSindbis viruses, RossRiver virus, and Venezuelan, Eastern & WesternEquine encephalitis, and rubivirus, including Rubella virus. Theflaviviridae family includes dengue, yellow fever, Japaneseencephalitis, St. Louis encephalitis and tick borne encephalitisviruses. Other target antigens may be generated from the Hepatitis C orthe coronavirus family, which includes a number of non-human virusessuch as infectious bronchitis virus (poultry), porcine transmissiblegastroenteric virus (pig), porcine hemagglutinating encephalomyelitisvirus (pig), feline infectious peritonitis virus (cats), feline entericcoronavirus (cat), canine coronavirus (dog), and human respiratorycoronaviruses, which may cause the common cold and/or non-A, B or Chepatitis. Within the coronavirus family, target antigens include the E1(also called M or matrix protein), E2 (also called S or Spike protein),E3,(also called HE or hemagglutin-elterose) glycoprotein (not present inall coronaviruses), or N (nucleocapsid). Still other antigens may betargeted against the rhabdovirus family, which includes the generavesiculovirus (e.g., Vesicular Stomatitis Virus), and the generallyssavirus (e.g., rabies). Within the rhabdovirus family, suitableantigens may be derived from the G protein or the N protein. The familyfiloviridae, which includes hemorrhagic fever viruses such as Marburgand Ebola virus, may be a suitable source of antigens. The paramyxovirusfamily includes parainfluenza Virus Type 1, parainfluenza Virus Type 3,bovine parainfluenza Virus Type 3, rubulavirus (mumps virus),parainfluenza Virus Type 2, parainfluenza virus Type 4, Newcastledisease virus (chickens), rinderpest, morbillivirus, which includesmeasles and canine distemper, and pneumovirus, which includesrespiratory syncytial virus (e.g., the glyco- (G) protein and the fusion(F) protein, for which sequences are available from GenBank).

[0140] The influenza virus is classified within the familyorthomyxovirus and is a suitable source of antigen (e.g., the HAprotein, the Ni protein). The bunyavirus family includes the generabunyavirus (California encephalitis, La Crosse), phlebovirus (RiftValley Fever), hantavirus (puremala is a hemahagin fever virus),nairovirus (Nairobi sheep disease) and various unassigned bungaviruses.The arenavirus family provides a source of antigens against LCM andLassa fever virus. The reovirus family includes the genera reovirus,rotavirus (which causes acute gastroenteritis in children), orbiviruses,and cultivirus (Colorado Tick fever, Lebombo (humans), equineencephalosis, blue tongue).

[0141] The retrovirus family includes the sub-family oncorivirinal whichencompasses such human and veterinary diseases as feline leukemia virus,HTLVI and HTLVII, lentivirinal (which includes human immunodeficiencyvirus (HIV), simian immunodeficiency virus (SIV), felineimmunodeficiency virus (FIV), equine infectious anemia virus, andspumavirinal). Among the lentiviruses, many suitable antigens have beendescribed and can readily be selected. Examples of suitable HIV and SIVantigens include, without limitation the gag, pol, Vif, Vpx, VPR, Env,Tat, Nef, and Rev proteins, as well as various fragments thereof. Forexample, suitable fragments of the Env protein may include any of itssubunits such as the gp120, gp160, gp41, or smaller fragments thereof,e.g., of at least about 8 amino acids in length. Similarly, fragments ofthe tat protein may be selected. [See, U.S. Pat. No. 5,891,994 and U.S.Pat. No. 6,193,981.] See, also, the HIV and SIV proteins described in D.H. Barouch et al, J. Virol., 75(5):2462-2467 (March 2001), and R. R.Amara, et al, Science, 292:69-74 (6 Apr. 2001). In another example, theHIV and/or SIV immunogenic proteins or peptides may be used to formfusion proteins or other immunogenic molecules. See, e.g., the HIV-1 Tatand/or Nef fusion proteins and immunization regimens described in WO01/54719, published Aug. 2, 2001, and WO 99/16884, published Apr. 8,1999. The invention is not limited to the HIV and/or SIV immunogenicproteins or peptides described herein. In addition, a variety ofmodifications to these proteins have been described or could readily bemade by one of skill in the art. See, e.g., the modified gag proteinthat is described in U.S. Pat. No. 5,972,596. Further, any desired HIVand/or SIV immunogens may be delivered alone or in combination. Suchcombinations may include expression from a single vector or frommultiple vectors. Optionally, another combination may involve deliveryof one or more expressed immunogens with delivery of one or more of theimmunogens in protein form. Such combinations are discussed in moredetail below.

[0142] The papovavirus family includes the sub-family polyomaviruses(BKU and JCU viruses) and the sub-family papillomavirus (associated withcancers or malignant progression of papilloma). The adenovirus familyincludes viruses (EX, AD7, ARD, O.B.) which cause respiratory diseaseand/or enteritis. The parvovirus family feline parvovirus (felineenteritis), feline panleucopeniavirus, canine parvovirus, and porcineparvovirus. The herpesvirus family includes the sub-familyalphaherpesvirinae, which encompasses the genera simplexvirus (HSVI,HSVII), varicellovirus (pseudorabies, varicella zoster) and thesub-family betaherpesvirinae, which includes the genera cytomegalovirus(Human CMV), muromegalovirus) and the sub-family gammaherpesvirinae,which includes the genera lymphocryptovirus, EBV (Burkitts lymphoma),infectious rhinotracheitis, Marek's disease virus, and rhadinovirus. Thepoxvirus family includes the sub-family chordopoxvirinae, whichencompasses the genera orthopoxvirus (Variola (Smallpox) and Vaccinia(Cowpox)), parapoxvirus, avipoxvirus, capripoxvirus, leporipoxvirus,suipoxvirus, and the sub-family entomopoxvirinae. The hepadnavirusfamily includes the Hepatitis B virus. One unclassified virus which maybe suitable source of antigens is the Hepatitis delta virus. Still otherviral sources may include avian infectious bursal disease virus andporcine respiratory and reproductive syndrome virus. The alphavirusfamily includes equine arteritis virus and various Encephalitis viruses.

[0143] The present invention may also encompass immunogens which areuseful to immunize a human or non-human animal against other pathogensincluding bacteria, fungi, parasitic microorganisms or multicellularparasites which infect human and non-human vertebrates, or from a cancercell or tumor cell. Examples of bacterial pathogens include pathogenicgram-positive cocci include pneumococci; staphylococci; andstreptococci. Pathogenic gram-negative cocci include meningococcus;gonococcus. Pathogenic enteric gram-negative bacilli includeenterobacteriaceae; pseudomonas, acinetobacteria and eikenella;melioidosis; salmonella; shigella; haemophilus (Haemophilus influenzae,Haemophilus somnus); moraxella; H. ducreyi (which causes chancroid);brucella; Franisella tularensis (which causes tularemia); yersinia(pasteurella); streptobacillus moniliformis and spirillum. Gram-positivebacilli include listeria monocytogenes; erysipelothrix rhusiopathiae;Corynebacterium diphtheria (diphtheria); cholera; B. anthracis(anthrax); donovanosis (granuloma inguinale); and bartonellosis.Diseases caused by pathogenic anaerobic bacteria include tetanus;botulism; other clostridia; tuberculosis; leprosy; and othermycobacteria.

[0144] Examples of specific bacterium species are, without limitation,Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcusagalactiae, Streptococcus faecalis, Moraxella catarrhalis, ,Helicobacterpylori, Neisseria meningitidis, Neisseria gonorrhoeae,Chlamydia trachomatis, Chlamydia pneumoniae, Chlamydia psittaci,Bordetella pertussis, Salmonella typhi, Salmonella typhimurium,Salmonella choleraesuis, Escherichia coli, Shigella, Vibrio cholerae,Corynebacterium diphtheriae, Mycobacterium tuberculosis, Mycobacteriumavium, Mycobacterium intracellulare complex, Proteus mirabilis, Proteusvulgaris, Staphylococcus aureus, Clostridium tetani, Leptospirainterrogans, Borrelia burgdorferi, Pasteurella haemolytica, Pasteurellamultocida, Actinobacillus pleuropneumoniae and Mycoplasma gallisepticum.

[0145] Pathogenic spirochetal diseases include syphilis; treponematoses:yaws, pinta and endemic syphilis; and leptospirosis. Other infectionscaused by higher pathogen bacteria and pathogenic fungi includeactinomycosis; nocardiosis; cryptococcosis (Cryptococcus), blastomycosis(Blastomyces), histoplasmosis (Histoplasma) and coccidioidomycosis(Coccidiodes); candidiasis (Candida), aspergillosis (Aspergillis), andmucormycosis; sporotrichosis; paracoccidiodomycosis, petriellidiosis,torulopsosis, mycetoma and chromomycosis; and dermatophytosis.Rickettsial infections include Typhus fever, Rocky Mountain spottedfever, Q fever, and Rickettsialpox. Examples of mycoplasma andchlamydial infections include: mycoplasma pneumoniae; lymphogranulomavenereum; psittacosis; and perinatal chiamydial infections. Pathogeniceukaryotes encompass pathogenic protozoans and helminths and infectionsproduced thereby include: amebiasis; malaria; leishmaniasis (e.g.,caused by Leishmania major); trypanosomiasis; toxoplasmosis (e.g.,caused by Toxoplasma gondii); Pneumocystis carinii; Trichans; Toxoplasmagondii; babesiosis; giardiasis (e.g., caused by Giardia); trichinosis(e.g., caused by Trichomonas); filariasis; schistosomiasis (e.g., causedby Schistosoma); nematodes; trematodes or flukes; and cestode (tapeworm)infections. Other parasitic infections may be caused by Ascaris,Trichuris, , Cryptosporidium, and Pneumocystis carinii, among others.

[0146] Many of these organisms and/or toxins produced thereby have beenidentified by the Centers for Disease Control [(CDC), Department ofHeath and Human Services, USA], as agents which have potential for usein biological attacks. For example, some of these biological agents,include, Bacillus anthracis (anthrax), Clostridium botulinum and itstoxin (botulism), Yersinia pestis (plague), variola major (smallpox),Francisella tularensis (tularemia), and viral hemorrhagic fevers[filoviruses (e.g., Ebola, Marburg], and arenaviruses [e.g., Lassa,Machupo]), all of which are currently classified as Category A agents;Coxiella burnetti (Q fever); Brucella species (brucellosis),Burkholderia mallei (glanders), Burkholderia pseudomallei (meloidosis),Ricinus communis and its toxin (ricin toxin), Clostridium perfringensand its toxin (epsilon toxin), Staphylococcus species and their toxins(enterotoxin B), Chlamydia psittaci (psittacosis), water safety threats(e.g., Vibrio cholerae, Crytosporidium parvum), Typhus fever (Richettsiapowazekii), and viral encephalitis (alphaviruses, e.g., Venezuelanequine encephalitis; eastern equine encephalitis; western equineencephalitis); all of which are currently classified as Category Bagents; and Nipan virus and hantaviruses, which are currently classifiedas Category C agents. In addition, other organisms, which are soclassified or differently classified, may be identified and/or used forsuch a purpose in the future. It will be readily understood that theviral vectors and other constructs described herein are useful todeliver antigens from these organisms, viruses, their toxins or otherby-products, which will prevent and/or treat infection or other adversereactions with these biological agents.

[0147] Administration of the vectors of the invention to deliverimmunogens against the variable region of the T cells elicit an immuneresponse including CTLs to eliminate those T cells. In RA, severalspecific variable regions of TCRs which are involved in the disease havebeen characterized. These TCRs include V-3, V-14, V-17 and Vα-17. Thus,delivery of a nucleic acid sequence that encodes at least one of thesepolypeptides will elicit an immune response that will target T cellsinvolved in RA. In MS, several specific variable regions of TCRs whichare involved in the disease have been characterized. These TCRs includeV-7 and Vα-10. Thus, delivery of a nucleic acid sequence that encodes atleast one of these polypeptides will elicit an immune response that willtarget T cells involved in MS. In scleroderma, several specific variableregions of TCRs which are involved in the disease have beencharacterized. These TCRs include V-6, V-8, V-14 and Vα-16, Vα-3C, Vα-7,Vα- 14, Vα-15, Vα-16, Vα-28 and Vα-12. Thus, delivery of a recombinantsimian adenovirus that encodes at least one of these polypeptides willelicit an immune response that will target T cells involved inscleroderma.

[0148] Further, desirable immunogens include those directed to elicitinga therapeutic or prophylactic anti-cancer effect in a vertebrate host,such as, without limitation, those utilizing a cancer antigen ortumor-associated antigen including, without limitation, prostatespecific antigen, carcino-embryonic antigen, MUC-1, Her2, CA-125 andMAGE-3.

[0149] The examples provided below specifically illustrate theadvantages of the methods and compositions of the invention utilizing arecombinant simian adenoviral vector from which an immunogenic peptideof rabies (glycoprotein G) or human immunodeficiency virus-1 (a modifiedgag protein) is expressed. Another desirable embodiment utilizes asimian adenovirus carrying an immunogenic peptide from human papillomavirus (e.g., E6, E7 and/or L1 (Seedorf, K. et al, Virol., 145:181-185(1985))]. However, the invention is not limited to these sources ofimmunogens.

[0150] C. Ad-Mediated Delivery Methods

[0151] The therapeutic levels, or levels of immunity, of the selectedgene can be monitored to determine the need, if any, for boosters.Following an assessment of CD8+ T cell response, or optionally, antibodytiters, in the serum, optional booster immunizations may be desired.Optionally, the recombinant simian adenoviral vectors of the inventionmay be delivered in a single administration or in various combinationregimens, e.g., in combination with a regimen or course of treatmentinvolving other active ingredients or in a prime-boost regimen. Avariety of such regimens have been described in the art and may bereadily selected.

[0152] For example, prime-boost regimens may involve the administrationof a DNA (e.g., plasmid) based vector to prime the immune system tosecond, booster, administration with a traditional antigen, such as aprotein or a recombinant virus carrying the sequences encoding such anantigen. See, e.g., WO 00/11140, published Mar. 2, 2000, incorporated byreference. Alternatively, an immunization regimen may involve theadministration of a recombinant simian adenoviral vector of theinvention to boost the immune response to a vector (either viral orDNA-based) carrying an antigen, or a protein. In still anotheralternative, an immunization regimen involves administration of aprotein followed by booster with a vector encoding the antigen.

[0153] In one embodiment, the invention provides a method of priming andboosting an immune response to a selected antigen by delivering aplasmid DNA vector carrying said antigen, followed by boosting with arecombinant simian adenoviral vector of the invention. In oneembodiment, the prime-boost regimen involves the expression ofmultiproteins from the prime and/or the boost vehicle. See, e.g., R. R.Amara, Science, 292:69-74 (Apr. 6, 2001) which describes a multiproteinregimen for expression of protein subunits useful for generating animmune response against HIV and SIV. For example, a DNA prime maydeliver the Gag, Pol, Vif, VPX and Vpr and Env, Tat, and Rev from asingle transcript. Alternatively, the SIV Gag, Pol and HIV-1 Env isdelivered in a recombinant adenovirus construct of the invention. Stillother regimens are described in WO 99/16884 and WO 01/54719.

[0154] However, the prime-boost regimens are not limited to immunizationfor HIV or to delivery of these antigens. For example, priming mayinvolve delivering with a first chimp vector of the invention followedby boosting with a second chimp vector, or with a composition containingthe antigen itself in protein form. In one example, the prime-boostregimen can provide a protective immune response to the virus, bacteriaor other organism from which the antigen is derived. In another desiredembodiment, the prime-boost regimen provides a therapeutic effect thatcan be measured using convention assays for detection of the presence ofthe condition for which therapy is being administered.

[0155] The priming composition may be administered at various sites inthe body in a dose dependent manner, which depends on the antigen towhich the desired immune response is being targeted. The invention isnot limited to the amount or situs of injection(s) or to thepharmaceutical carrier. Rather, the regimen may involve a priming and/orboosting step, each of which may include a single dose or dosage that isadministered hourly, daily, weekly or monthly, or yearly. As an example,the mammals may receive one or two doses containing between about 10 μgto about 50 μg of plasmid in carrier. A desirable amount of a DNAcomposition ranges between about 1 μg to about 10,000 μg of the DNAvector. Dosages may vary from about 1 μg to 1000 μg DNA per kg ofsubject body weight. The amount or site of delivery is desirablyselected based upon the identity and condition of the mammal.

[0156] The dosage unit of the vector suitable for delivery of theantigen to the mammal is described herein. The vector is prepared foradministration by being suspended or dissolved in a pharmaceutically orphysiologically acceptable carrier such as isotonic saline; isotonicsalts solution or other formulations that will be apparent to thoseskilled in such administration. The appropriate carrier will be evidentto those skilled in the art and will depend in large part upon the routeof administration. The compositions of the invention may be administeredto a mammal according to the routes described above, in a sustainedrelease formulation using a biodegradable biocompatible polymer, or byon-site delivery using micelles, gels and liposomes. Optionally, thepriming step of this invention also includes administering with thepriming composition, a suitable amount of an adjuvant, such as aredefined herein.

[0157] Preferably, a boosting composition is administered about 2 toabout 27 weeks after administering the priming composition to themammalian subject. The administration of the boosting composition isaccomplished using an effective amount of a boosting compositioncontaining or capable of delivering the same antigen as administered bythe priming DNA vaccine. The boosting composition may be composed of arecombinant viral vector derived from the same viral source (e.g.,adenoviral sequences of the invention) or from another source.Alternatively, the “boosting composition” can be a compositioncontaining the same antigen as encoded in the priming DNA vaccine, butin the form of a protein or peptide, which composition induces an immuneresponse in the host. In another embodiment, the boosting compositioncontains a DNA sequence encoding the antigen under the control of aregulatory sequence directing its expression in a mammalian cell, e.g.,vectors such as well-known bacterial or viral vectors. The primaryrequirements of the boosting composition are that the antigen of thecomposition is the same antigen, or a cross-reactive antigen, as thatencoded by the priming composition.

[0158] In another embodiment, the simian adenoviral vectors of theinvention are also well suited for use in a variety of otherimmunization and therapeutic regimens.

[0159] Such regimens may involve delivery of simian adenoviral vectorsof the invention simultaneously or sequentially with Ad vectors ofdifferent serotype capsids, regimens in which adenoviral vectors of theinvention are delivered simultaneously or sequentially with non-Advectors, regimens in which the adenoviral vectors of the invention aredelivered simultaneously or sequentially with proteins, peptides, and/orother biologically useful therapeutic or immunogenic compounds. Suchuses will be readily apparent to one of skill in the art.

[0160] Dosages of the viral vector will depend primarily on factors suchas the condition being treated, the age, weight and health of thepatient, and may thus vary among mammalian (including human) patients.Advantageously, the unexpected potency of the recombinant simian (e.g.,chimpanzee) adenoviruses of the invention permits the use significantlylower amount of the recombinant chimpanzee adenovirus to provide aneffective amount to induce the desired immunogenic effect (e.g.,induction of a predetermined level of CD8+ T cells). For example, aneffective dose of the recombinant simian adenovirus may be provided by10⁴ pfu and 10⁶ pfu of the chimpanzee adenovirus. However, higher dosesmay be readily selected, e.g., depending upon the selected route ofdelivery. For example, the viral vector may be delivered in an amountwhich ranges from about 100 μL to about 100 ml, and more preferably,about 1 mL to about 10 mL, of carrier solution containing concentrationsof ranging from about 1×10⁴ plaque forming 30 units (pfu) to about1×10¹³ pfu virus/ml, and about 1×10⁹ to about 1×10¹¹ pfu/ml virus, basedupon an 80 kg adult weight. A preferred dosage is estimated to be about50 ml saline solution at 2×10¹⁰ pfu/ml. A preferred dose is from about 1to about 10 ml carrier (e.g., saline solution) at the aboveconcentrations. The therapeutic levels, or levels of immunity, of theselected gene can be monitored to determine the need, if any, forboosters. Following an assessment of CD8+ T cell response, oroptionally, antibody titers, in the serum, optional boosterimmunizations may be desired. Optionally, the recombinant simianadenoviruses may be delivered using a prime-boost regimen. A variety ofsuch regimens have been described in the art and may be readilyselected. One particularly desirable method is described in WO 00/11140,published Mar. 2, 2000, incorporated by reference.

[0161] In one desirable embodiment, the invention provides a method ofpreferentially inducing a CD8+ T cell response to a humanimmunodeficiency virus in a subject by delivering a recombinant simianadenovirus comprising a modified gag protein. The modified gag proteinillustrated in the examples below has been optimized, e.g., as describedin U.S. Pat. No. 5,972,596. The coding and protein sequences arereproduced herein in SEQ ID NO:45 and SEQ ID NO:46. See, also, G. Meyerset al., Eds. Human retroviruses and AIDS. A compilation and analysis ofnucleic acid and amino acid sequences (Los Alamos National Laboratory,Los Alamos, N.M. 1991). However, any of a variety of methods to improveexpression of the gag protein, or any other selected immunogen orantigen as described herein, are known to those of skill in the art andmay be utilized, e.g., humanization of the HIV-1 gag codon sequences,removal of the HIV-1 gag splice site, insertion of additional leadersequences upstream of the HIV-1 gag codon sequences, insertion of aKozak sequence upstream of the HIV-1 gag codon sequences. The selectionof the optimization method is not a limitation of the present invention.Alternatively, the method of the invention may be used to deliver arecombinant simian adenovirus carrying an HIV envelope protein, or anHIV pol, to the subject. One desirable HIV envelope protein is HIVglycoprotein 120 for which sequences are available from GenBank.However, other suitable viral envelope proteins may be utilized. Thesequence for HIV-1 pol is known, as are a variety of modified polsequences. See, e.g., U.S. Pat. No. 5,972,596 and R. Scheider et al, J.Virol, 71(7):4892-4903 (July 1997). In another desirable embodiment, theinvention provides a method of preferentially inducing a CD8+ T cellresponse to a tumor-associated protein specific for a selectedmalignancy by delivering a recombinant simian adenovirus comprising atumor-associated protein to the subject. Such a protein includescellular oncogenes such as mutated ras or p53.

[0162] Still another desirable embodiment involves delivering arecombinant simian adenovirus comprising a protein derived from humanpapilloma virus for prevention of infection therewith and for treatmentand prophylaxis of associated conditions.

[0163] The following examples are provided to illustrate the inventionand do not limit the scope thereof. One skilled in the art willappreciate that although specific reagents and conditions are outlinedin the following examples, modifications can be made that are meant tobe encompassed by the spirit and scope of the invention.

EXAMPLE 1 Creation of an E1 Deleted Vector Based on ChimpanzeeAdenovirus C68

[0164] A replication defective version of C68 was isolated for use ingene transfer. The classic strategy of creating a recombinant with E1deleted, by homologous recombination in an E1 expressing cell line waspursued. The first step was creation of a plasmid containing m.u. 0through 1.3 followed by addition of a minigene expressing enhanced greenfluorescent protein (GFP) from a CMV promoter and C68 sequence spanning9-16.7 m.u. This linearized plasmid was cotransfected into an E1expressing cell line with Ssp I-digested C68 plasmid (SspI cuts at 3.6m.u. leaving 4644 bp for homologous recombination). Experiments wereinitially conducted with 293 cells which harbor E1 from human Ad5 withthe hope that this would suffice for transcomplementation. Indeed,plaques formed which represented the desired recombinant. The resultingvector was called C68-CMV-GFP.

[0165] The strategy for generating recombinants was modified to enableefficient and rapid isolation of recombinants. First, the alkalinephosphatase DNA in the initial shuttle vector was replaced with aprokaryotic GFP gene driven by the prokaryotic promoter from lacZ. Thisallowed efficient screening of bacterial transformations when attemptingto incorporate a desired eukaryotic RNA pol II transcriptional unit intothe shuttle vector. The resulting transformation can be screened forexpression of GFP; white colonies are recombinants while green coloniesare residual parental plasmid.

[0166] A green-white selection has been used to screen the products ofcotransfection for the isolation of human Ad5 recombinants (A. R. Daviset al, Gene Thera., 5:1148-1152 (1998)); this was adapted to the C68system. The initial shuttle vector was revised to include extended3′sequences from 9 to 26 MU. This vector was cotransfected with viralDNA from the original C68-CMV-GFP isolate that had been restricted withXba I, which cuts at MU 16.5 allowing for 9.5 Kb of overlap forhomologous recombination. The resulting plaques were screened under aphase contrast fluorescent microscope for non-fluorescing isolates thatrepresent the desired recombinants. This greatly simplified screening incomparison to the standard methods based on structure or transgeneexpression.

[0167] A. Shuttle Plasmid

[0168] To construct a plasmid shuttle vector for creation of recombinantC68 virus, the plasmid pSP72 (Promega, Madison, Wis.) was modified bydigestion with Bgl II followed by filling-in of the ends with Klenowenzyme (Boehringer Mannheim, Indianapolis, Ind.) and ligation with asynthetic 12 bp Pac I linker (New England Biolabs, Beverly, Mass.) toyield pSP72-Pac. A 456 bp Pac I/SnaB I fragment spanning map unit (m.u.or MU) 0-1.3 of the C68 genome was isolated from the pNEB-BamE plasmidcontaining BamHI E fragment of the C68 genome and cloned into Pac I andEcoR V treated pSP72-Pac to yield pSP-C68-MU 0-1.3. A minigene cassetteconsisting of the cytomegalovirus early promoter driving lacZ with aSV40 poly A signal was separated from pCMVP (Clontech, Palo Alto,Calif.) as a 4.5 kb EcoRI/SalI fragment and ligated to pSP-C68-MU 0-1.3restricted with the same set of enzymes, resulting in pSP-C68-MU0-1.3-CMVLacZ.

[0169] For the initial step in the isolation of the 9-16.7 MU region ofC68, both pGEM-3Z (Promega, Madison, Mich.) and pBS-C68-BamF weredouble-digested with BamHII and Sph I enzymes. Then the 293 bp fragmentfrom pBS-C68-BamF was ligated with pGEM-3Z backbone to form pGEM-C68-MU9-9.8. A 2.4 kb fragment including the C68 MU 9.8-16.7 was obtained fromthe pBS-C68 BamHB clone after XbaI digestion, filling in reaction andsubsequent BamHI treatment and cloned into BamHI/SmaI double digestedpGEM-C68-MU 9-9.8 to generate pGEM-C68-MU 9-16.7. The C68 9-16.7 m.u.region was isolated from pGEM-C68-MU 9-16.7 by digestion with EcoRI,filling in of the ends with Kienow enzyme (Boehringer Mannheim,Indianapolis, Ind.), ligation of a synthetic 12 bp HindIII linker (NEB)and then digestion with HindIII. This 2.7 kb fragment spanning the C68MU 9-16.7 was cloned into the HindIII site of pSP-C68-MU 0-1.3-CMVlacZto form the final shuttle plasmid pC68-CMV-LacZ. In addition, an 820 bpalkaline phosphatase (AP) cDNA fragment was isolated from pAdCMVALP (K.J. Fisher, et al., J. Virol., 70:520-532 (1996)) and exchanged for lacZat Not I sites of pC68-CMV-lacZ, resulting in pC68-CMV-AP.

[0170] B. Construction of Recombinant Virus

[0171] To create the E1-deleted recombinant C68-CMVEGFP vector, apC68-CMV-EGFP shuttle plasmid was first constructed by replacing thelacZ transgene in pC68-CMV-lacZ with the enhanced green fluorescentprotein (EGFP) gene. The replacement cloning process was carried out asthe follows. An additional NotI restriction site was introduced into the5′ end of the EGFP coding sequence in the pEGFP-1 (Clontech, Palo Alto,Calif.) by BamHI digestion, filling in reaction and ligation of a 8 bpsynthetic NotI linker (NEB). After NotI restriction of both constructs,the EGFP sequence was isolated from the modified pEGFP-1 and used toreplace the lacZ gene in the pC68-CMV-lacZ. The pC68-CMVEGFP construct(3 μg) was co-transfected with Ssp I-digested C68 genomic DNA (1 μg)into 293 cells for homologous recombination as previously described (G.Gao, et al, J. Virol, 70:8934-8943 (1996)). Green plaques visualized byfluorescent microscopy were isolated for 2 rounds of plaquepurification, expansion and purification by CsCl gradient sedimentation(G. Gao, et al, cited above).

[0172] In an attempt to apply the convenient green/white selectionprocess (A. R. Davis, et al., Gene Thera., 5:1148-1152 (1998)) toconstruction of recombinant C68 vectors, a 7.2 kb fragment spanning 9 to36 MU was isolated from the pBSC68-BamB plasmid by treatment with AgeIand BsiwI restriction endonucleases and cloned into Asp718 and AgeIsites of pC68-CMV-AP shuttle plasmid, resulting in a new plasmid calledpC68CMV-AP-MU36. A further modification was made to remove 26 to 36 m.u.from pC68CMV-AP-MU36 by Eco47III and NruI digestions. The new shuttleplasmid called pC68CMV-AP-MU26 has a shorter region for homologousrecombination (i.e., 16.7-26 MU) 3′ to the minigene. To make arecombinant C68 vector, alkaline phosphatase (AP) is replaced with thegene of interest. The resulting pC68CMV-Nugene-MU26 construct isco-transfected with Xba I (16.5 MU) restricted C68-CMVGFP viral DNA into293 cells, followed by top agar overlay. The recombinant virus plaques(white) are generated through the homologous recombination in the regionof 16.7-26 MU which is shared between pC68CMV-Nugene construct and C68viral backbone; the recombinants which form white plaques are selectedfrom green plaques of uncut C68-CMVGFP virus.

[0173] The green/white selection mechanism was also introduced to theprocess of cloning of the gene of interest into the pC68 shuttleplasmid. The AP gene in both pC68CMV-AP-MU36 and pC68CMV-AP-MU26 wasreplaced with a cassette of prokaryotic GFP gene driven by the lacZpromoter isolated from pGFPMU31 (Clontech, Palo Alto, Calif.). Thus,white colonies of bacterial transformants will contain the recombinantplasmid. This green/white selection process for bacterial coloniescircumvented the need for making and characterizing large numbers ofminipreped DNAs and so further enhanced the efficiency in creatingrecombinant C68 vectors.

EXAMPLE 2 Expression of Antigen (Gag secretion) in TK⁻ Cells Infectedwith Simian Adenovirus Vaccine Constructs

[0174] Adenoviral recombinants of the chimpanzee strain 68 (Adchimp68)and the human strain 5 (Adhu5) carrying a nucleotide sequence modifiedversion of a truncated form of the gag gene of HIV-1 clade B wereconstructed as described (in Example 1 and Z. Q. Xiang, et al, Virol.219, 200 (1996)). Transcripts of structural proteins of HIV-1, includinggag, contain genetic instability elements, which require the presence ofrev protein for nuclear export and efficient expression in the cytoplasm(S. Schwartz et al., J Virol 66, 7176 (1992); S.Schwartz, et al, J Virol66, 150-159 (1992); G. Nasioulas et al., J Virol 68, 2986 (1994)).Adenoviruses rely on nuclear transcription and thus require rev forexpression of HIV-1 proteins. To circumvent Rev dependency, acodon-modified sequence of gag from which genetic instability elementshad been removed by site directed mutagenesis (R. Schneider et al., JVirol 71, 4892 (1997); S. Schwartz et al., J Virol 66, 7176 (1992); S.Schwartz, et al., J Virol 66, 150 (1992)) was inserted into theadenoviral vector. The introduced gene encodes the truncated p37gagprotein (p17 and p24 regions). The truncated gag protein does not formviral particles and is partially secreted into the supernatant oftransfected human cells (R. Schneider et al., J Virol 71, 4892 (1997)).The mutated gag constructs have been used in vaccination experiments andresult in the generation of cellular and humoral immune responses inmice and primates (J. T. Qiu et al. J Virol 73, 9145. (1999)).

[0175] The Adchimp68 and the Adhu5 recombinants were both generated andpropagated on 293 cells transfected with the E1 of adenovirus of thehuman strain 5. The inventors have found that this heterologous E1 issuitable for complementing the E1-deleted Adchimp68 virus recombinantsthus reducing the risk of recombination and reversion toreplication-competent wild-type virus.

[0176] The presence of gag protein in the TK⁻ culture supernatants wasanalyzed by Western blotting using mouse monoclonal antibodies to gag.TK⁻ cells (1×10⁶) were infected for 48 hrs with Adhu5gag37 orAdchimp68gag37 virus (10 pfu per cell). Additional TK⁻ cells wereinfected with an Adhu5 or an Adchimp68 construct expressing theglycoprotein of rabies virus. Proteins in the culture supernatant wereseparated on a 12% denaturing polyacrylamide gel and transferred byelectroblotting to a PVDF membrane. The blot was stained with themonoclonal antibody 183-H12-5C to HIV-1 p24 (B. Chelsebro, et al. J.Virol. 66: 6547 (1992).

[0177] The two adenoviral recombinant clones (Adhu5gag37,Adchimp68gag37) carrying this modified sequence of gag expressed thetransgene product at comparable levels as shown by Western Blotanalysis. A protein of the expected size (37 kDa) that bound to amonoclonal antibody to gag of HIV-1 was detected in the supernatants ofTK⁻ cells infected with 10 plaque forming units (pfu) of eitheradenovirus gag recombinant. Control cells infected with Adhu5 orAdchimp68 recombinant expressing glycoprotein of rabies virus(Adhu5rab.gp and Adchimp68.gp) failed to produce this protein.

EXAMPLE 3 Induction of CD8+ T Cell Responses to Gag in Mammals by SimianAdenovirus

[0178] The following experiment demonstrates that the splenocytes ofmice injected intramuscularly (i.m.) with either the Adhu5gag37 or theAdchimp68gag37 recombinant responded to an immunodominant epitope (B.Doe and C. M. Walker, AIDS 10, 793 (1996)) of the gag protein bycytokine, i.e., interferon (IFN)-γ, release, as well as by target celllysis.

[0179] A. Cytokine Release Assay

[0180] Groups of 3 Balb/c mice were immunized i.m. with 2×10⁵, 2×10⁶ or2×10⁷ pfu of Adchimp68gag37 virus, 2×10⁶ pfu of Adhu5L1 virus (H. C. J.Ertl, et al., J. Virol, 63:2885 (1989)), 2×10⁶ pfu of Adhu5 gag37 virusor 2×10⁷ pfu of VVgag virus. Splenocytes were tested for CD8⁺ T cellresponse to gag 10 days later. To assay cytokine (IFN-γ) production,splenocytes (b 1×10 ⁶/sample) were cultured for 5 hrs at 37° C. with 3μg/ml of the AMQMLKETI peptide (SEQ ID NO:40) which carries theimmunodominant CD8⁺ T cell epitope for the H-2^(d) haplotype and 1 μg/mlBrefeldin A (GolgiPlug, PharMingen, San Diego, Calif.) in 96 wellround-bottom microtiter plate wells in Dulbeccos modified Eagles medium(DMEM) supplemented with 2% fetal bovine serum (FBS) and 10⁻⁶M2-mercaptoethanol. Cells were washed with PBS and incubated for 30 minat 4□C with a FITC labeled antibody to murine CD8. Cells were washed andpermeabilized in 1X Cytofix/Cytoperm (PharMingen) for 20 min at 4° C.Cells were washed 3 times with Perm/Wash (PharMingen) and incubated inthe same buffer for 30 min at 4° C. with a PE labeled antibody to murineIFN-γ. After washing, cells were examined by two-color flow cytometryand data were analyzed by WinmDi software. The number in the right handcorner shows the percent of CD8⁺ cells over all CD8⁺ T cells thatstained positive for INF-γ.

[0181] Seven to ten days after a single immunization, a sizable fractionof the entire splenic CD8⁺ T cell population produced IFN-γ in responseto the gag peptide. Primary splenocytes assayed without further in vitroexpansion lysed H-2 compatible target cells pre-treated with the gagpeptide. Gag-specific CD8⁺ T cell activity was superior uponimmunization with the Adchimp68 construct, which achieved CD8⁺ T cellfrequencies to gag of 16-19% of the entire splenic CD8⁺ cell population.The response was dose-dependent as shown for the Adchimp68gag37 viruswhere a low dose of 2×10⁵ pfu of virus still elicited frequencies ofnearly 10%. The Adhu5gag37 recombinant induced optimal frequencies of˜9% at 2×10⁶ pfu. These frequencies were not significantly enhanced uponincreasing the dose of this vaccine (data not shown). A vaccinia virusrecombinant expressing full-length gag (VVgag, designated vDKI in S.Chacarabarti et al. Mol. Cell. Biol. 5, 3403 (1985)) stimulated farlower frequencies of CD8⁺ T cells by intracellular cytokine staining.

[0182] B. Lysis of Target Cells.

[0183] Splenocytes from mice immunized 10 days previously with a singledose of the adenoviral recombinants as described in A or two doses ofthe VVgag recombinant the first given i.m. followed 2 weeks later by anintraperitoneal injection were tested in a 5 hr ⁵¹Cr-release assay atvaried effector to target cell ratios on 1×10⁴ P815 cells that had beentreated for 16-24 hrs at room temperature with either the peptide to gag(filled squares) or the control peptide 31 D (X) delineated from thesequence of the rabies virus nucleoprotein (H. C. J. Ertl et al., J.Virol. 63 : 2885 (1989)). Two immunizations with the VVgag vaccine wererequired to induce detectable T cell-mediated gag-specific primarycytolysis.

[0184] C. Kinetics of the CD8⁺ T Cell Response to Gag

[0185] Groups of 4 Balb/c mice were immunized with 5×10⁶ pfu ofAdhu5gag37 or Adchimp68gag37 virus. Splenocytes were harvested 6-12 dayslater and tested for IFN-γ production and target cell lysis as describedabove. The kinetics of the CD8⁺ T cell response to gag elicited by thetwo adenovirus recombinants differed. The response to gag presented bythe Adhu5gag37 virus peaked 2-4 days earlier than the CD8⁺ T cellresponse to the Adchimp68gag37 recombinant.

EXAMPLE 4 Effect of Prior Exposure to Human Adenovirus on SimianAdenovirus Vaccine

[0186] To study the impact of previous exposure to the common humanstrain 5 of adenovirus, mice were immunized with a single dose of anAdhu5 recombinant expressing an irrelevant antigen (human papillomavirus L1). Two weeks later mice were vaccinated either with theAdhu5gag37 or the Adchimp68gag37 vaccine.

[0187] More particularly, mice were immunized i.m. with 10⁸ pfu of theAdhu5L1 vaccine. Two weeks later Adhu5-immune as well as naive mice wereinjected with 2×10⁶ or 2×10⁷ pfu of Adhu5gag37 or Adchimp68gag37recombinants (4-5 mice per group). Additional groups of Adhu5LI immuneor naïve mice were immunized with 2×10⁶ pfu of the Adhu5gag37 or theAdchimp68gag37 virus. Nine days later mice were injectedintraperitoneally with 10⁶ pfu of a vaccinia virus recombinantexpressing full-length gag. Mice were sacrificed five days after thevaccinia virus injection.

[0188] Mice pre-immune to Adhu5 virus failed to respond to gag aftervaccination with the Adhu5gag37 vaccine. They showed frequencies of CD8⁺gag-specific T cells similar to those seen in control mice andcorrespondingly, their splenocytes failed to lyse gag expressing targetcells. In contrast, the CD8⁺ T cell response to gag was only slightlydecreased in Adhu5-immune mice vaccinated with the Adchimp68gag37construct. Frequencies of CD8⁺ T cells to gag were reduced by only ˜30%and the cytolytic activity of splenocytes was lowered by ˜50% comparingdifferent effector to target cell ratios.

[0189] Thus, both adenoviral recombinants induce frequencies of CD8⁺ Tcells to gag, surpassing those elicited by previously described vaccinessuch as naked DNA or poxvirus recombinants (S.Schwartz, et al, J Virol66, 150-159 (1992)). Frequencies were also higher than those generallyseen in chronically infected individuals (D. H. Barouch et al. Proc.Natl. Acad Sci USA. 97, 4192 (2000); T. U. Vogel et al. J. Immunol. 164,4968 (2000); P. A. Goepfert et al. J. Virol. 74, 10249 (2000); C. R.Rinaldo Jr. et al. AIDS Res. & Hum. Retr. 14:1423 (1998)). These resultsemphasize the potency of adenoviral recombinant vaccines.

EXAMPLE 5 Effect of Priming and Boosting of CD8⁺ T Cells to Antigen

[0190] Primary splenocyctes from the cells of naïve or Adhu5-immune miceimmunized with 2×10⁷ pfu of Adhu5gag37 or Adchimp68gag37 virus werecompared with splenocytes from naïve or Adhu5 immune mice vaccinatedwith 2×10⁶ pfu of Adhu5gag37 or Adchimp68gag37 virus and then boostedwith 106 pfu of VVgag virus. Splenocytes were analyzed 5 days later forCD8 and intracellular IFN-γ. These assays were performed essentially asdescribed above, with the exception that there was no further in vitroculture for lysis of P815 cells treated with the gag peptide or thecontrol peptide 31D in a 5 hr ⁵¹Cr-release assay.

[0191] Priming or booster immunization with a heterologous vaccineconstruct, the VVgag recombinant, failed to restore the CD8 T cellresponse to gag presented by the Adhu5 recombinant vaccine. AlthoughAdhu5 vaccinated animals boosted with Adhu5gagp37 and VVgag showed asmuch as 7.1% of splenic CD8⁺ T cells to produce IFN-γ-in response to thegag these CD8⁺ T cells totally lacked cytolytic activity againstgag-presenting target cells. These results indicate that pre-exposure tothe antigens of the vaccine carrier had not only a quantitative but alsoa qualitative influence on the CD8⁺ T cell response to the transgeneproduct of the adenoviral recombinant. The CD8⁺ T cell response to gagin Adhu5 immune mice vaccinated with Adchimp68gag37 showed a boostereffect upon VVgag immunization similar to that seen in naive mice.

[0192] Frequencies of CD8⁺ T cells to gag as well as primary target celllysis could be augmented further by priming (not shown) or boosting witha heterologous vaccine carrier, such as the VVgag recombinant. Afteri.m. priming with the adenoviral recombinants followed 9 days later byan i.p. booster immunization with the VVgag, CD8⁺ gag-specific T cellsanalyzed 5 days post-prime comprised ˜40% of the entire splenic CD8⁺cell-population.

[0193] Pre-existing immunity to Adhu5 severely reduced the efficacy ofthe Adhu5gag37 vaccine but only slightly impaired the CD8⁺ T cellresponse to the Adchimp68gag37 virus. It was previously reported thatmice immunized to Adhu5 virus developed a reduced B cell response tovaccination with an Adhu5 vaccine to rabies virus. Increasing the doseof the vaccine or using a DNA vaccine expressing the same antigen ofrabies virus could readily circumvent the dampening effect of thepre-exposure to Adhu5 virus (Z. Q. Xiang, et al., J. Immunol. 162, 6716(1999)).

[0194] In contrast, the CD8⁺ T cell response to gag presented by theAdhu5 recombinant vaccine was abolished in Adhu5 immune mice and couldonly partially be restored by additional immunizations with aheterologous vaccine to gag. This may indicate induction of CD8⁺ T cellsto be more susceptible to interference by circulating virus neutralizingantibodies as compared to stimulation of B cells.

EXAMPLE 6 Production of Recombinant Adenoviruses Containing RabiesGlycoprotein

[0195] Adenoviruses of the human serotypes 2,4, 5, 7, 12 and thechimpanzee serotype 68 were propagated and titrated on human 293 cells.The recombinant adenoviruses based on the human serotype 5 expressingthe glycoprotein of the ERA serotype of rabies virus or the L1 proteinof the human papilloma virus (HPV)-16 have been described previously (Z.Q. Xiang, et al, Virology 219: 220-227 (1996); D. W. Kowalcyk, et al,(2001) Vaccine regimen for prevention of sexually transmitted infectionswith human papillomavirus type 16. Vaccine). An expression system basedon adenoviruses of the chimpanzee serotype 68 was developed as describedin Example 1.

[0196] Adenoviruses were propagated on E1 (derived from the humanserotype 5)-transfected 293 cells (F. L. Graham, et. al., J. Gen. Virol.36: 59-74 (1977)). Viruses were harvested by freeze thawing of thecells. For some experiments virus was purified by CsCl gradientpurification. For other experiments, cleared supernatant of the infectedcells necrotized through three rounds of freeze thawing was used.Viruses were titrated on 293 cells to determine plaque forming units(pfu).

[0197] The adenoviral recombinant of the chimpanzee 68 serotypeexpressing the rabies virus glycoprotein, termed Adchimp68rab.gp wasgenerated in 293 cells transfected with E1 of adenovirus human serotype5 as described in detail in this example. Viral clones were initiallyscreened by indirect immunofluorescence with the monoclonal antibody509-6 to a conformation-dependent epitope of the rabies virusglycoprotein. Upon selection of a stable adenoviral subclone, expressionof full-length rabies virus glycoprotein by the Ad.chimp68rab.gp virusin infected TK⁻ cells was confirmed by immunoprecipitation, as describedin the following example.

EXAMPLE 7 Expression of the Transgene Product by the AdenoviralRecombinants.

[0198] This example shows that the Adhu5 virus achieved markedly higherlevels of rabies virus glycoprotein expression in TK⁻ cells as comparedto the Adchimp68 construct. Transcript levels for this transgeneparalleled protein expression indicating that the difference wasunrelated to differences in post-translational modifications. TK⁻ cellsare CAR positive and rates of transduction by the viral serotypes shouldthus be comparable.

[0199] For use in these experiments, mammalian cells, i.e., baby hamsterkidney (BHK)-21 cells, E1-transfected 293 cells and TK⁻ cells, werepropagated in Dulbecco's modified Eagle's medium (DMEM) supplementedwith glutamine, Na-pyrovate, non-essential amino acids, HEPES buffer,antibiotic and 10% fetal bovine serum (FBS).

[0200] A. Immunoprecipitation

[0201] TK⁻ cells (10⁶ per sample) were infected with 5 pfu per cell ofeither the rabies virus glycoprotein expressing adenoviral recombinantsor control constructs expressing an unrelated viral antigen. After 48hrs cells were washed twice with sterile phosphate buffered saline (PBS)and then incubated for 90 min in serum-free medium prior to the additionof 20 μl of ³⁵S-labeled cystein and methionin (Promix, NEN, Boston,Mass.). After 4 hrs incubation, cells were washed with PBS and thentreated for 20 min with 1 ml of protease inhibitors containing RIPAbuffer. Cells and cell debris were removed from the wells, vortexedbriefly and centrifuged for 2 min at 12.000 rpm. The supernatant wasincubated for 90 min at 4° C. with 15 μl/ml of ascitic fluid containingthe 509-6 monoclonal antibody to the rabies virus glycoprotein. ProteinSepharose G was added at 75 μl per sample and incubated at 4° C. undermild agitation for 30 min. The samples were pelleted by centrifugationand washed 4 times with RIPA buffer. The pellets were resuspended in 80μl of loading buffer, boiled for 4 min. Samples (20 μ) were thenseparated over a 12% SDS-polyacrylamide (PAGE) gel in comparison to amolecular weight standard. Gels were dried onto filter papers which wereexposed for 48 hrs to a Kodak Scientific Imaging Film (X-Omat BlueXB-1).

[0202] The Adchimp68rab.gp recombinant expressed a protein of theexpected size that bound to the 509-6 antibody. The precipitate ofTK⁻cells infected with the Adhu5rab.gp virus showed a band of theidentical size that was absent in lysates from cells infected withadenoviral recombinants expressing an unrelated transgene product.Expression of the rabies virus glycoprotein was more pronounced in cellsinfected with the Adhu5rab.gp construct. The difference in expression ofthe transgene product may reflect pre-translational events such asdifferences in viral uptake, rate of transcription or transcriptstability. Alternatively, translational or post-translationaldifferences such as distinct side chain modifications may result inquantitative differences in serologically detectable protein.

[0203] To further distinguish between these two possibilities, the totalRNA was isolated from TK⁻ cells infected with either of the adenoviralrecombinants. Reverse transcribed mRNA to the rabies virus glycoproteinand a housekeeping gene was amplified by real-time PCR performed asdescribed in part B.

[0204] B. Real Time Reverse Transcription Polymerase Chain Reaction(PCR)

[0205] Confluent monolayers of TK⁻ cells were infected in duplicatesamples with 10 pfu of either of the adenoviral recombinants. Cells wereisolated 24 hrs later and RNA was extracted with the TRI reagentaccording to the manufacturer's instructions (Mol. Res. Center,Cincinnati, Ohio). The RNA was treated with RNAse-free DNAse, purifiedby phenol extraction and adjusted to 50 ng of RNA per sample. The RNAwas reverse transcribed and amplified with the Light Cycler-RNAamplification kit SYBR green (Roche, Mannheim, Germany; Z. He, et al,Virology 270: 146-1617 (2000)) using primers for the rabies virusglycoprotein (SEQ ID NO:41: 5′ AA GCA TTT CCG CCC AAC AC; SEQ ID NO:42:3′ GGT TAG TGG AGC AGT AGG TAG A) and the housekeeping geneglutaraldehyde-3-phosphate dehydrogenase (GAPDH) (SEQ ID NO: 43: 5′ GGTGAA GGT CGG TGT GAA CGG ATT T; SEQ ID NO:44: 3′ AAT GCC AAA GTT GTC ATGGAT GAC C).

[0206] The data in Table 1 provides the results. The data show the meanvalues for duplicate measurements ±SD. TABLE 1 Relative TranscriptQuantity Ratio Source of RNA GAPDH rab.gp (GAPDH/rab.gp) TK⁻,Adhu5rab.gp  3.2 ± .2 3494 ± 18 1082 TK⁻, 0.52 ± .01111  64 ± 6 64Adchimp68rab.gp

[0207] As shown by this data, the transgene transcripts adjusted tothose of the housekeeping gene showed a quantitative differencecomparable to that of serologically detectable protein.

[0208] In data not provided in this example, two other Adchimp68recombinants expressing the green fluorescent protein and acodon-modified truncated gag protein of the human immunodeficiencyvirus-1 were compared to the Adhu5 recombinants expressing the sametransgene products showed equivalent protein expression levels in TK⁻cells. From this it has been concluded that the reduced expression ofthe rabies virus glycoprotein by the Adchimp68 virus reflects adifference neither in viral uptake nor in rate of transcription, whichin both constructs is regulated by the same control elements.

EXAMPLE 8 Immunization of Mice Using a Rabies Virus Antigen.

[0209] The rabies virus-specific antibody response to theAd.chimp68rab.gp virus was compared to that of the Adhu5rab.gp virus ininbred and outbred strains of mice. Mice were injected with serialdilutions of either of the recombinants given s.c. or i.n. Sera wereharvested 14 days later and tested for antibodies to the rabies virusglycoprotein by an ELISA and a virus neutralization assay. Adenoviralrecombinants expressing an unrelated transgene, i.e., the gag of HIV-1(described in the Examples above) were used as controls. Theserecombinants failed to induce an antibody response to rabies virusdetectable by either assay. A more detailed discussion of this study andthe results follows.

[0210] Female 6-8 week old C3H/He and C57B1/6 mice were purchased fromJackson Laboratory, Bar Harbor Me. Outbred ICR mice were purchased fromCharles River (Wilmington, Mass.).

[0211] Mice were injected with varied doses of the adenoviruses or theadenoviral recombinants given in 100 μi of saline subcutaneously (s.c.)or in 50 μl intranasally (i.n.). Mice were challenged with rabies virusof the CVS-11 strain given at 10 mean lethal doses (LD₅₀)intracerebrally (i.c.). Rabies virus of the Evelyn Rokitniki-Abelseth(ERA) and the Challenge Virus Standard (CVS)-11 strain were propagatedon BHK-21 cells. ERA virus was purified over a sucrose gradient,inactivated by treatment with betapropionolactone and adjusted to aprotein concentration of 0.1 mg/mi. CVS-11 virus was titrated on BHK-21cells and by intracerebral injection of adult ICR mice (Z. Q. Xiang, Z.Q. & H. C. Ertl, J. Virol. Meth. 47: 103-16 (1994)). Upon challenge micewere checked every 24-48 hrs for at least 21 days. They were euthanizedonce they developed complete hindleg paralysis, which is indicative ofterminal rabies virus encephalitis.

[0212] The serological assays included enzyme linked immunoadsorbantassay (ELISA), isotype profile of antibodies, and virus neutralizationassays.

[0213] A. ELISA

[0214] Mice were bled a varied time intervals after immunization byretro-orbital puncture. Sera were prepared and tested for antibodies torabies virus on plates coated with 0.1 μg/well of inactivated rabiesvirus. Sera were tested for antibodies to adenovirus on plates coatedwith 0.1 μg/well of purified E1-deleted adenovirus recombinants to GFPof the human serotype 5 or the chimpanzee serotype 68. ELISAs wereperformed basically as described before (Z. Q. Xiang, et al, Virology219, 220-227 (1996)). Plates were coated over night. They were thenblocked for 24 hrs with PBS containing 3% of bovine serum albumin (BSA).After washing, sera diluted in PBS-3% BSA were added for 60 min. Afterwashing, a 1:100 dilution of alkaline phosphatase conjugated goat antimouse Ig (Cappel) was added for 1 hr on ice. After washing, substratewas added for 20-30 min at room temperature. Optical density was read at405 nm.

[0215] B. Isotypes of Antibodies

[0216] Isotypes of antibodies to rabies virus were determined by anELISA on plates coated with inactivated ERA virus using the CalbiochemHybridoma Subisotyping (LaJolla, Calif.) kit with some minor previouslydescribed modifications (Xiang, Virol, 1996, cited above).

[0217] The isotype profile of antibodies to also differed upon s.c.immunization but was comparable upon i.n. application of the twoadenoviral vaccines. Both recombinants, upon delivery by either route ofinoculation, elicited IgG2a antibodies to the antigen of rabies virus.

[0218] Both recombinants upon i.n. immunization and the Adhu5rab.gpvaccine upon s.c. administration induced a pronounced IgG I responseindicative of Th2 help, which was lacking in the response to theAd.chimp68rab.gp construct given s.c.

[0219] C. Neutralizing Antibodies

[0220] Sera were tested for neutralizing antibodies to rabies virus ofthe CVS-11 strain, which is antigenically closely related to the ERAstrain (Z. Q. Xiang, et al, Virology. 214: 398-404 (1996)). A WHOreference serum was used for comparison. Titers are expressed asInternational Units.

[0221] The Adchimp68rab.gp virus given s.c. induced a less potent B cellresponse to the transgene product as compared to the Adhu5rab.gpconstruct. The difference in magnitude of the antibody response, whichwas observed at all time points tested depended on the mouse strain andwas less pronounced in outbred ICR than in inbred C3H/He mice. Incontrast, upon i.n. immunization both vaccines induced comparable titersof antibodies as determined by ELISA and by virus neutralization assay.

[0222] The pronounced Th1 response to the Adchimp68rab.gp recombinantupon s.c. immunization contrasting with the more balanced Th1/Th2response upon injection of the Adhu5rab.gp argues for a difference inadjuvanticity. Upon application to the airways, the natural route ofinfection for Adhu5 virus and presumably for Adchimp68 viruses bothrecombinants induced antibody titers to the transgene product that werecomparable in magnitude and in their isotype profile. This suggests thatpostulated differences in tropism and/or adjuvanticity are tissuedependent, i.e., lacking or less pronounced in the airways as comparedto the subcutaneum.

EXAMPLE 9 Preferential Induction of Cytotoxic T Cell Response withRecombinant Chimpanzee Adenovirus

[0223] Vaccine-induced protection to rabies virus correlates withvirus-neutralizing antibodies (VNAs, F. L. Graham, et. al., J. Gen.Virol. 36, 59-74 (1977)). The studies with the rabies protein thusfocused on stimulation of this arm of the immune system. Throughout allof the experiments, mice were immunized with the Adchimp68rab.gp virusand, in parallel, with the previously described Adrab.gp virus based onthe human serotype 5. Within this application, this recombinant isreferred to as Adhu5rab.gp virus.

[0224] Both adenoviral recombinants induced protection to challenge withrabies virus. C3H/He mice immunized with 5×10⁶ pfu of either of theadenoviral recombinants given s.c. remained disease-free when challenged3 weeks later with 10 mean lethal doses (LD₅₀) of rabies virus of theCVS strain. This rabies virus strain is antigenically closely related tothe ERA strain but is more virulent in rodents. At a lower vaccine doseof 5×10⁵ pfu, the Adhu5rab.gp virus still provided complete protectionwhile a small percentage of Adchimp68rab.gp-immunized mice succumbed tothe infection. Further reduction of the vaccine dose resulted in loss ofefficacy of the Adchimp68rab.gp vaccine. Upon i.n. immunization, bothvaccines provided complete protection if given at 5×10⁵ pfu. At a lowerdose of 5×10⁴ pfu 50% of mice vaccinated with the Adhu5rab.gp vaccinedeveloped progressive disease while those immunized with this dose ofthe Adchimp68rab.gp recombinant were protected. All of the miceimmunized with adenoviral recombinants of either serotype expressing anunrelated antigen or with 5×10³ pfu of either of the adenoviralrecombinants to the rabies virus glycoprotein developed a fatal rabiesencephalitis.

EXAMPLE 10 The Effect of Pre-Existing Immunity to Different Serotypes ofHuman Adenoviruses on the Antibody Response to Rabies Virus.

[0225] To test if pre-exposure to any of the common serotypes of humanadenoviruses (e.g., human serotype 2, 4, 5, 7 and 12) would inhibit theantibody response to the Adchimp68rab.gp vaccine, groups of C3H/He micewere immunized with 4×10⁸ pfu of replication-competent adenoviruses ofthe human serotypes 2, 4, 5, 7 or 12 or the chimpanzee serotype 68 (thelatter serotype was E1-deleted). Two weeks later, mice were vaccinateds.c. with either Adhu5rab.gp or Adchimp68rab.gp virus. The Adhu5rab.gprecombinant was used at a dose of 2×10⁵ pfu per mouse, theAdchimp68rab.gp recombinant, which given s.c. only induces a marginalantibody response in C3H/He mice at such a low dose was injected at2×10⁷ pfu per mouse. Sera were harvested 2 weeks later and tested forantibodies to the rabies virus glycoprotein by an ELISA. The rabiesvirus-specific response to Adhu5rab.gp was slightly superior in naïvemice to that elicited to the Adchimp68 virus. The response toAdhu5rab.gp virus was completely inhibited in Adhu5 pre-immune mice.Some reduction was also seen in mice pre-immune to adenovirus of thehuman serotypes 4, 2, 7 and 12. The response was not affected in micethat had been pre-exposed to the Adchimp68 virus. The response to theAdchimp68rab.gp virus was strongly inhibited in mice that werepre-immune to the homologous virus. Mice that had previously encounteredadenovirus of the human serotype 2 showed a slight reduction of theantibody response to the rabies virus antigen presented by the Adchimp68vaccine. Mice inoculated with any of the other serotypes of humanadenoviruses developed antibody titers to rabies upon Adchimp68rab.gpvirus that were either similar or increased in magnitude compared tothose in mice that were naïve prior to vaccination. In particular, micepre-immune to Adhu5 virus developed higher antibody titers uponvaccination with the Adchimp68rab.gp construct which might reflect thepresence of cross-reactive T helper cells that promoted the B cellresponse to the transgene product.

[0226] To further determine if at equal vaccine doses theAdchimp68rab.gp vaccine induced superior antibody titers as compared tothe Adhu5rab.gp virus in mice pre-immune to Adhu5 virus, a vaccinetitration experiment was conducted. Groups of C3H/He mice were immunizeds.c. with 4×10⁸ pfu of an E1-deleted adenoviral recombinant to the L1antigen of HPV-16. Mice were vaccinated 2 weeks later with eitherAdhu5rab.gp or Adchimp68rab.gp virus given s.c. at varied doses. Micewere bled 2 weeks later and serum antibody titers to rabies virus weredetermined by an ELISA (not shown) and a virus neutralization assay.Neither assay showed a significant reduction for the antibody responseto the Adchimp68rab.gp construct in Adhu5-immune mice. The severity ofthe reduction of antibody titers to rabies virus presented by the Adhu5construct in mice pre-immune to the homologous virus depended on thevaccine dose. The antibody response to lower doses of vaccine was moreaffected than the response to higher vaccine doses. VNA titers weresubstantially more reduced than the ELISA titers. Titers of VNAs to thehighest vaccine dose were halved in mice pre-immune to Adhu5 virus whileat the two lower vaccine doses titers were reduced by more than 20 fold.At any of the doses tested, the Adchimp68rab.gp recombinant inducedhigher VNA titers to rabies in Adhu5 pre-immune mice compared to thoseachieved by an equal dose of the Adhu5rab.gp vaccine. The detrimentaleffect of pre-existing immunity to Adhu5 on the efficacy of the Adhu5vaccine was demonstrated further in a protection experiment. Naïve miceimmunized with 2×10⁵ pfu of Adhu5rab.gp or Adchimp68rab.gp virus werecompletely protected to challenge with CVS-11 virus. The majority (65%)of Adhu5 pre-immune mice immunized with this dose of the Adhu5rab.gpvaccine succumbed to a rabies virus infection while those vaccinatedwith the same dose of the Adchimp68rab.gp virus remained protected.Increasing the dose of the Adhu5rab.gp virus to 2×10⁶ pfu per mouserestored the efficacy of the vaccine.

[0227] The antibody response to the transgene product expressed by theAdchimp68 recombinant was not affected by pre-existing immunity tocommon human adenovirus serotypes, which inhibits the response to thecorresponding recombinant of the human serotype 5. Upon pre-immunizationwith replication-competent viruses, the immune response to theAdhu5rab.gp vaccine was abolished in Adhu5 pre-immune mice and reducedin mice pre-immune to other human serotypes of adenovirus such as 2 and4. The response to the Adchimp68 recombinant was as expected inhibitedin mice pre-immune to the homologous virus. This is not of clinicalconcern as Adchimp68 virus does not circulate in the human populationand common human serotypes do not share neutralizing epitopes withAdchimp68 virus.

[0228] Pre-exposure to replication-defective Adhu5 virus also reducedthe antibody response to the rabies virus glycoprotein presented by theAdhu5 recombinants although the impact was not as severe as in micepreviously infected with replication-competent virus. Sera from micepre-immune to replication-defective Adhu5 virus developed reduced butreadily detectable antibodies to rabies virus upon immunization with theAdhu5rab.gp vaccine. Increasing the dose of the Adhu5rab.gp constructcould in part circumvent the impact of pre-existing immunity.Vaccine-induced protection against rabies virus requires VNAs, whichwere not induced as efficiently in pre-immune mice by the Adhu5 vaccineespecially when used at lower doses. In Adhu5 pre-immune mice the VNAresponse to the Adchimp68rab.gp construct was superior at all dosestested to that of the Adhu5 vaccine thus more than compensating for theslightly lower potency of this vaccine upon s.c. immunization.

[0229] Adchimp68 recombinants thus provide an attractive alternative asa vaccine carrier for use in humans. As shown here they are efficaciouseven when applied at low doses of 2×10⁵ pfu through non invasive routesof administration such as the upper airways. Mucosal immunization byi.n. application has the added advantage of favoring induction ofresponses of the common mucosal immune system, which is distinct from,albeit interconnected with the central immune system targeted byinjected vaccines.

EXAMPLE 11 Chimpanzee C68 Virus Stock and Replication

[0230] Examples 11 through 15 which follow provide additionalcharacterization of the chimpanzee C68. It will be appreciated by one ofskill in the art that this information can be readily used in theconstruction of novel recombinant chimpanzee adenoviral constructs.

[0231] The C68 virus stock was obtained from ATCC (Rockville, Md.) andpropagated in 293 cells (ATCC) cultured in DMEM (Sigma, St. Louis, Mo.)supplemented with 10% fetal calf serum (FCS; Sigma or Hyclone, Logan,Utah) and 1% Penicillin-Streptomycin (Sigma). Infection of 293 cells wascarried out in DMEM supplemented with 2% FCS for the first 24 hours,after which FCS was added to bring the final concentration to 10%.Infected cells were harvested when 100% of the cells exhibitedvirus-induced cytopathic effect (CPE), collected, and concentrated bycentrifugation. Cell pellets were resuspended in 10 mM Tris (pH8.0), andlysed by 3 cycles of freezing and thawing. Virus preparations wereobtained following 2 ultra centrifuge steps on cesium chloride densitygradients and stocks of virus were diluted to 1×10¹² particles/ml in 10mM Tris/100 mM NaCl/50% glycerol and stored at −70° C.

EXAMPLE 12 Cloning and Sequencing of Viral Genomic DNA

[0232] Genomic DNA was isolated from the purified virus preparationfollowing standard methods and digested with a panel of 16 restrictionenzymes following the manufacturer=s recommendations. Except as noted,all restriction and modifying enzymes were obtained from BoehringerMannheim, Indianapolis, Ind. Genomic DNA was digested with BamHI, PstI,SalI, HindIII or XbaI and the fragments were subcloned into plasmids (K.L. Berkner and P. A. Sharp, Nucl. Acids Res., 11:6003-20 (1983)). Afterdeproteination, synthetic 10 bp PacI linkers (New England Biolabs,Beverly, Mass.) were double digested with PacI and BamHI, or PstI.

[0233] The Pstl, BamHI and HindIII clones generated from C68 areillustrated in FIG. 1, parts C, D and E, respectively. The fragmentsindicated by the shaded boxes were not cloned, but the sequence of theentire genome has been determined through sequencing overlapping clonesand viral DNA directly (unshaded boxes). The cloned fragments aredescribed in Table 2. TABLE 2 C68 plasmid clones and insert sizes InsertSize 5′ End (base Fragment Fragment Map 3′ End Construct Name pairs) 5′End 3′ End Unit Map Unit Pst-I Fragments C68-Pst-A 6768 24784 3155167.9% 86.4% pBS: C68-Pst-B 6713 4838 11550 13.2% 31.6% pBS: C68-Pst-C5228 14811 20038 40.6% 54.9% pBS: C68-Pst-D 2739 12072 14810 33.1% 40.6%pBS: C68-Pst-E 2647 20039 22685 54.9% 32.1% pBS: C68-Pst-F 1951 3204633996 87.8% 93.1% PNEB: C68-Pst-G 1874 1 1874 0.0% 5.1% pBS: C68-Pst-H1690 23094 24783 63.2% 67.9% pBS: C68-Pst-I 1343 33997 35339 93.1% 96.8%PNEB: C68-Pst-J 1180 35340 36519 96.8% 100.0% pBS: C68-Pst-K 1111 27633873 7.6% 10.6% pBS: C68-Pst-L 964 3874 4837 10.6% 13.2% pBS: C68-Pst-M888 1875 2762 5.1% 7.6% pBS: C68-Pst-N 408 22686 23093 62.1% 63.2%C68-Pst-O 380 31666 32045 86.7% 87.7% pBS: C68-Pst-P 285 11551 1183531.6% 32.4% C68-Pst-Q 236 11836 12071 32.4% 33.1% pBS: C68-Pst-R 11431552 31665 86.4% 86.7% BamHI Fragments C68-Bam-A 16684 19836 3651954.3% 100.0% pBS: C68-Bam-B 8858 3582 12439 9.8% 34.1% pBS: C68-Bam-C4410 12440 16849 34.1% 46.1% pBS: C68-Bam-D 2986 16850 19835 46.1% 54.3%PNEB: C68-Bam-E 2041 1 2041 0.0% 5.6% pBS: C68-Bam-F 1540 2042 3581 5.6%9.8% HindIII Fragments pBR: C68-Hind-B 9150 23471 32620 64.3% 89.3% pBS= pBluescript SK + clone pNEB = pNEB 193 clone pBR = pBR322 clone Noprefix = fragment not cloned

[0234] Chimpanzee adenovirus, C68, was obtained from ATCC and propagatedin human 293 cells. Viral genomic DNA was isolated from purified virionsusing established procedures (A. R. Davis, etal., Gene Thera.,5:1148-1152 (1998)) and digested with a panel of restriction enzymes;the data were consistent with previous studies (data not shown) (G. R.Kitchingman, Gene, 20:205-210 (1982); Q. Li and G. Wadell, Arch Virol.101:65-77 (1998); R. Wigand, et al., Intervirology. 30:1-9 (1989)).Restriction fragments spanning the entire genome of C68 were subclonedinto plasmids. A schematic drawing of the C68 genome is shown in FIG.1A, and the Pst-1, BamHI and HindIII fragments that were cloned intoplasmid vectors are indicated by the unshaded boxes, in FIGS. 1B, 1C,and 1D, respectively. The cloned fragments, fragment sizes and genomicposition are also listed in Table 2. Both plasmid clones and genomic DNAwere used as templates for sequencing. The genome was sequenced byprimer walking in both directions and each base was included in anaverage of approximately four reactions.

[0235] The C68 genome is 36521 bp in length [see, U.S. Pat. No.6,083,716]. Preliminary comparison with GenBank sequences indicatedvarying degrees of similarity with other human and animal adenovirusesalong the entire length of the viral genome. Regions with homology toall of the previously described adenoviral genetic units, early regions1-4 and the major late genes, were found in the C68 genome (FIG. 1A).DNA homology between C68 and the human adenoviruses that have beencompletely sequenced, Ad2 (NC001405), Ad5 (NC001405), Ad12 (NC001460),Ad17 (NC002067) and Ad40 (NC01464), was used to order the clones. Theopen reading frames (ORF) were determined and the genes were identifiedbased on homology to other human adenoviruses. All of the majoradenoviral early and late genes are present in C68. The invertedterminal repeats (ITR=s) are 130 bp in length.

EXAMPLE 13 Analysis of C68 Sequence

[0236] The complete nucleotide sequence of every member of theMastadenovirus genus accessible from GenBank, including isolates fromdifferent species, were screened for identity to C68. The Ad4 minigenomewas assembled from the following GenBank sequences: Left-hand ITR(J01964); E1A region (M14918); DNA pol and pTP (X74508, 74672); VARNA-I, II (U10682); 52, 55K (U52535); pVII (U70921); hexon (X84646);endoprotease (M16692); DNA-binding protein (M12407); fiber (X76547);right-hand ITR (J01965). The Ad7 composite genome was created from thefollowing sequence data: Mu 3-21 (X03000); VA RNA-I, II, pTP & 52, 55K(U52574); penton (AD001675); pVl, hexon and endoprotease (AF065065);DNA-binding protein (K02530); E3 and fiber region (AF104384); right-handITR (V00037).

[0237] The amino acid sequence alignment was generated with Clustal X,edited with Jalview (http://www.ebi.ac.uk/˜michele/jalview/), andanalyzed with Boxshade(http://www.ch.embnet.org/software/BOX_form.html). Publicly availablehexon protein sequences from all human adenovirus serotypes wereinitially aligned to identify the set showing the highest homology toC68.

[0238] The nucleotide sequence and predicted amino acid sequences of allsignificant open reading frames in the C68 genome were compared to knownDNA and protein sequences. The nucleotide sequence of C68 is compared tosequences of Ad 2, 4, 5, 7, 12, 17 and 40. In agreement with previousrestriction analysis (Kitchingman, cited above; Li and Wadell, citedabove) C68 is most similar to human Ad4 (subgroup E).

[0239] The EIA region of C68 extends from the TATA box at nt 480 to thepoly A addition site at 1521. The consensus splice donor and acceptorsites are in the analogous position of the human Ad counterparts, andthe 28.2K and 24.8K proteins are similar in size to the human Adproteins. The ORF for the smallest E1A protein of C68 is predicted toencode 101 residues as opposed to approximately 60 amino acids for otheradenoviruses. There is a TTA codon at residue 60 for C68 where otheradenoviruses often have a TGA stop codon. The first 60 residues of C68E1A 100R protein have 85% identity to the Ad4 homolog.

[0240] The C68 genome encodes genes for the four E1B proteins, 20.5K,54.7K, 10.1K and 18.5K as well as pIX. All five C68 encoded proteins aresimilar in size to that of other Ad EIB and pIX proteins. The Ad4homolog of the E1B 21K protein has only 142 amino acids, where C68 has186 residues and other human adenoviruses have 163-178 residues. The C68and Ad4 proteins share 95% identity over the first 134 aa, then thesimilarity ends and the Ad4 protein terminates at 142 amino acids.

[0241] The C68 genome encodes homologs of the E2A 55K DNA bindingprotein and the Iva2 maturation protein, as well as the E2B terminalprotein and the DNA polymerase. All of the E2 region proteins aresimilar in size to their human Ad counterparts, and the E2B proteins areparticularly well conserved. The C68 E2B 123.6K DNA polymerase ispredicted to be 1124 residues, while Ad4 is predicted to have 1193although the other human adenoviruses have smaller polymerases. Residues1-71 of the Ad4 polymerase have no similarity to any other Adpolymerase, and it is possible that this protein actually initiates atan internal ATG codon. From amino acids 72-1193, Ad4 and C68 polymeraseshave 96% amino acid identity.

[0242] The E3 regions of human adenoviruses sequenced so far exhibitconsiderable sequence and coding capacity variability. Ad40 has five E3region genes, Ad12 has six, C68 and Ad5 have seven, Ad38 has eight andAd3 as well as Ad7 (subgroup B human adenoviruses) have nine putative E3region genes. The Ad4 E3 region has not yet been sequenced. Incomparison with the E3 region of Ad35, all 7 E3 gene homologs wereidentified in the C68 genome (C. F. Basler and M. S. Horwitz, Virology,215: 165-177 (1996)).

[0243] The C68 E4 region has 6 ORFs and each is homologous to proteinsin the human Ad5, 12 and 40 E4 region. The E4 nomenclature is confusingbecause the ORF2 homologs of C68, Ad12 and Ad40are approximately 130residues, while in Ad5 there are two ORFs encoding proteins of 64 and 67residues with homology, respectively, to the amino and carboxy terminalends of the larger ORF2 proteins. ORF5 has been omitted in ournomenclature because the ₅th ORF in the E4 region is homologous to thewidely studied ORF6 protein of human Ad5.

[0244] The major late promoter and the tri-partite leader sequences ofthe C68 genome were located. ORFs with the potential to encode the 15major late proteins were located. All of the C68 late proteins aresimilar in size to their human Ad counterparts. The percent amino acididentity between chimpanzee and human Ad late proteins variesconsiderably. The C68 fiber protein is predicted to have 90% amino acididentity with the Ad4 protein, but much less similarity to the otherhuman Ad fiber proteins. The CAR binding site in the fiber knob ispresent in C68.

EXAMPLE 14 Virus Neutralizing Antibody Assays

[0245] Several studies were performed to determine if there iscross-reactivity between type specific antisera of C68 and humanadenovirus. The neutralizing activity of sera was tested as follows.Panels of sera from normal human subjects (N=50), rhesus monkeys (N=52)and chimpanzees (N=20) were evaluated for neutralizing antibodiesagainst Ad5 and C68 based vectors using 293 cells as an indicator cellline. Sera collected from individual humans, rhesus monkeys, orchimpanzees were inactivated at 56□C for 30 minutes. Aserial dilution ofeach sample (1:10, 1:20, 1:40, 1:80, 1:160, 1:320 in 100 μl of DMEMcontaining 10% FCS) was added to equal amounts of H5.01OCMVEGFP (1000PFU/well) or C68CMVEGFP virus and incubated at 4□C for two hrs. Onehundred and fifty microliters of the mixture were transferred onto 2×10293 cells in 96 well flat bottom plates. Control wells were infectedwith equal amounts of virus (without addition of serum). Samples wereincubated at 37° C. in 5% CO₂ for 48 hrs and examined under afluorescent microscope. Sample dilutions that showed >50% reduction ofgreen-fluorescent foci as compared to infected controls were scoredpositive for neutralizing antibodies.

[0246] As expected, approximately 35% of normal human subjectsdemonstrated neutralizing antibody against Ad5, a frequency much higherthan observed in sera of rhesus monkeys and chimpanzee. Neutralizingantibody to C68 was observed in 80% of chimpanzee and only 2% of normalhuman subjects or rhesus monkeys. Titers of neutralizing antibodies inthe non-target species were generally low.

[0247] To further evaluate cross-reactivity of C68 with human adenovirusvectors, mice were immunized with 2×10⁷ plaque forming units (pfu) of Ad2, 4, 5, 7 and 12 as well as C68. Sera were harvested 2 weeks later andtested for antibodies that neutralized either Ad5 or C68 vectors.Neutralizing antibody to Ad5 vector was only detected in animalsimmunized with Ad5. Importantly, the only animals with neutralizingantibody to C68 vector were those immunized with C68 vector; none of thehuman serotypes tested, including Ad4, generated antibodies in mice thatneutralized C68 in vitro.

[0248] Important to the utility of C68 vector in human trials is theabsence of neutralizing antibody in the human population. In our study,a screen of 50 normal human subjects failed to detect any significantneutralizing antibodies (>1:10) using the same assay that showedneutralizing antibodies in >50% of chimpanzees. Furthermore, sera ofmice immunized with multiple human Ad serotypes including Ad4, did notneutralize infection with C68.

[0249] In another study, groups of ten to twenty ICR mice werevaccinated with varied doses of the Adhu5rab.gp or the AdC68rab.gpvaccine given subcutaneously (s.c.), intranasally (i.n.) or orally (peros). Mice were bled 21 days later and viral neutralizing antibody (VNA)titers expressed as international units were determined. Mice werechallenged 4 weeks after vaccinated with 10 mean lethal doses of CVS-24virus applied directly into the central nervous system. VNA Titers (%survival upon challenge) Vaccine Dose 5 × 10⁷ 5 × 10⁶ 5 × 10⁵ 5 × 10⁴Adhu5rab.gp, s.c. 972 (100) 324 (100) 108 (100)  12 (100) AdC68rab.gp,s.c. 240 (100)  36 (100)  12 (80)   8 (80) Adhu5rab.gp, i.n. nt 162(100) 162 (100)  18 (50) AdC68rab.gp, i.n. nt  54 (100) 162 (100)  18(50) 2 × 10⁷ 2 × 10⁶ 2 × 10⁵ 2 × 10⁴ Adhu5rab.gp, per os 108 (100)  54(88)  18 (80)   4 (30) AdC68rab.gp, per os 108 (100)  36 (78)  12 (55)0.2 (0)

[0250] These data demonstrate that the AdC68 construct unexpectedlyinduces a better protective antibody response at low doses intranasallythan human type 5.

EXAMPLE 15 Structural Analysis of Hexon Proteins

[0251] The absence of neutralizing antibodies between C68 and humanserotypes compelled us to more carefully evaluate structural differencesin the regions of hexon presumed to harbor type specific epitopes.Previous studies have suggested that these epitopes are located withinthe 7 hypervariable regions of hexon determined by Crawford-Miksza andSchnurr (J. Virol, 70:1836-1844 (1996)). A comparison of the amino acidsequences of hexon proteins between C68 and several human adenovirusesis shown in FIG. 2. Indeed, C68 is substantially dissimilar insignificant regions of these hypervariable sequences. More detailedmodeling of the three dimensional structure of hexon of C68 wasperformed to map the unique sequences. Models of hexon structures fromC68 and Ad4 were generated based on the x-ray crystal structures ofhexons for Ad2 and Ad5.

[0252] The X-ray crystal structures of Ad5 hexon (Protein Data Bankidentifier 1RUX) (J. J. Rux and R. M. Burnett, Mol. Ther. 1:18-30(2000)), and that for Ad2 (F. K. Athappilly, et al, J. Mol. Biol., 242:430-455 (1994)), have been further refined to yield the current hexonmodels (Rux and Burnett, to be published elsewhere). Models of thehomologous C68 and Ad4 hexons were initially produced using theSwiss-PdbViewer protein-modeling environment (N. Guez and M. C. Peitsch,Electrophoresis, 18:2714-2723 (1997)). Its automated procedure was usedto align the C68 and Ad4 hexon amino acid sequences to those of the Ad2and Ad5 hexon crystal structures. The sequence alignments were used toguide the threading of the model sequences onto the known molecularstructures. The side chain positions of residues not seen in the knownstructures were selected from a library of side chain protomers. Theseinitial molecular models were then manually adjusted to improve theautomated alignment by moving gaps to exposed variable regions and byoptimizing the packing of side chains. The positions of external loopsegments not observed in the Ad2 and Ad5 template structures were eitherselected from a library of known loop structures or fitted manually. Theconformation of each model was further refined by energy minimizationusing the molecular mechanics program CHARMM (B. R. Brooks, et al, J.Comp. Chem., 4:187-217 (1983)). The structures of these C68 and Ad4hexon models were then aligned and a new sequence alignment calculated.The differences between the two structurally aligned hexon sequenceswere used to color images of the homology models. Graphical imagesprepared within the Swiss-PdbViewer program were exported and renderedwith the Persistence of Vision Ray Tracer program (POV-Ray 2000, Version3.1 g).

[0253] While the overall C68 sequence is very similar to that of Ad4hexon, the differences between the two sequences are primarily focusedin the DE1 and FG1loops, and these contain all seven hypervariableregions. It is the DE1, FG1, and FG2 loops, each from a differentsubunit, that intimately associate to form the tower domains at the topof the trimeric molecule. The hexon towers form much of the exteriorsurface of the virion and are the sites of antibody attachment. As thesides and base of the hexons pack together within the capsid, theseregions are shielded from antibody binding and their sequences areconserved. In contrast, the sequences of C68 and Ad4 are quite differentin the hexon towers. This immediately explains why antibodies raised toeither of these viruses do not cross-react.

EXAMPLE 16 Viral Propagation

[0254] The Pan5 [ATCC Accession No. VR-591], Pan6 [ATCC Accession No.VR-592], and Pan7 [ATCC Accession No. VR-593] viruses, originallyisolated from lymph nodes from chimpanzees, were propagated in 293 cells[ATCC CRL1573]. Typically, these cells are cultured in Dulbecco'sModified Eagles Medium (DMEM; Sigma, St. Louis, Mo.) supplemented with10% fetal calf serum (FCS) [Sigma or Hyclone, Logan, Utah] and 1%Penicillin-Streptomycin (Sigma). Infection of 293 cells is carried outin DMEM supplemented with 2% FCS for the first 24 hours, after which FCSis added to bring the final concentration to 10%. Infected cells areharvested when 100% of the cells exhibit virus-induced cytopathic effect(CPE), and are then collected, and concentrated by centrifugation. Cellpellets are resuspended in 10 mM Tris (pH 8.0), and lysed by 3 cycles offreezing and thawing. Virus preparations are obtained following twoultra centrifugation steps on cesium chloride density gradients andstocks of virus are diluted to 1 to 5×10¹² particles/ml in 10 mMTris/100 mM NaCI/50% glycerol and stored at −70° C.

[0255] The ability of 293 cells to propagate these adenoviruses exceededexpectations which were based on knowledge of other non-human adenovirusserotypes. Virus Yield (virus particles produced in 8 × 10⁸ cells) Pan58.8 × 10¹³ Pan6 1.6 × 10¹⁴ Pan7 8.8 × 10¹³

EXAMPLE 17 Characterization of Viral Genomic DNA

[0256] Genomic DNA was isolated from the purified virus preparations ofExample 16 and digested with HindIII or BamHI restriction enzymesfollowing the manufacturers' recommendations. The results (not shown)revealed that that the PanS, Pan6, Pan7 genomes of the invention and thepublished Pan 9 (C68) genome show different restriction patterns, andthus, are distinct from each other.

[0257] The nucleotide sequences of Pan5, Pan6 and Pan7 were determined.The nucleotide sequence of the top strand of Pan5 DNA is reported in SEQID NO: 1. The nucleotide sequence of the top strand of Pan6 DNA isreported in SEQ ID NO: 5. The nucleotide sequence of the top strand ofPan7 DNA is reported in SEQ ID NO: 9.

[0258] Regulatory and coding regions in the viral DNA sequences wereidentified by homology to known adenoviral sequences using the “ClustalW” program described above at conventional settings. See the tablesabove providing the adenoviral sequences. Open reading frames weretranslated and the predicted amino acid sequences examined for homologyto previously described adenoviral protein sequences, Ad4, Ad5, Ad7,Ad12, and Ad40.

[0259] Analysis of the sequence revealed a genome organization that issimilar to that present in human adenoviruses, with the greatestsimilarity to human Ad4. However, substantial differences in the hexonhypervariable regions were noted between the chimpanzee adenoviruses andother known adenoviruses, including AdHu4. These differences fit wellwith the serological cross-reactivity data that has been obtained (seebelow).

[0260] An alignment of a portion of the hexon sequences is shown inFIG. 1. The portion shown is from the region of the hexon thatcorresponds to the outwardly disposed extended loops DE1 and FG1 wherethe most variability between serotypes is observed. An interveningportion that contributes to the base of the hexon (corresponding toresidues 308-368 of the published AdC68 sequence; U.S. Pat. No.6,083,716), and is highly conserved between serotypes, is also present.The following table summarizes the pair-wise comparisons of the aminoacids in the hexon proteins. Comparison Hexon amino-acid #1 #2Similarity (%) AdC5 AdC7 99.0 AdC5 AdC68 98.3 AdC5 AdC6 88.0 AdC5 AdC184.9 AdC6 AdC7 87.7 AdC6 AdC68 87.3 AdC6 AdC1 84.9 AdC7 AdC68 97.5 AdC7AdC1 84.8 AdC68 AdC1 84.9

[0261] Analysis of the fiber knob domain (which is responsible forreceptor binding) of the chimpanzee adenoviruses shows an overallsimilarity in structure (FIG. 2).

[0262] The degree of sequence similarity between the E1 proteins ofhuAd5 and C68 (see Tables below) is similar to that between huAdS andPan-5, Pan-6, and Pan-7. Comparison E1a (13S) amino-acid #1 #2 identity(%) AdHu5 AdC5 36.6 AdHu5 AdC6 28.5 AdHu5 AdC7 34.9 AdHu5 AdC68 35.6AdHu5 AdC1 35.6 AdC5 AdC6 68.3 AdC5 AdC7 96.9 AdC5 AdC68 80.4 AdC5 AdC151.3 AdC6 AdC7 69.3 AdC6 AdC68 59.4 AdC6 AdC1 37.7 AdC7 AdC68 81.5 AdC7AdC1 51.0 AdC68 AdC1 54.9

[0263] Sequence Identity with human Ad5 E1b Small T E1b Large T ProteinProtein C68 47.3% 55.8% Pan-5 43.2% 54.5% Pan-6 45.3% 54.5% Pan-7 46.4%53.8%

[0264] Replication-defective versions of AdC5, AdC6 and AdC7 werecreated by molecular cloning methods described in the following examplesin which minigene cassettes were inserted into the place of the E1a andE1b genes. The molecular clones of the recombinant viruses were rescuedand grown up in 293 cells for large-scale purification using thepublished CsCl sedimentation method [K. Fisher et al., J. Virol., 70:520(1996)]. Vector yields were based on 50 plate (150 mm) preps in whichapproximately 1×10⁹ 293 cells were infected with the correspondingviruses. Yields were determined by measuring viral particleconcentrations spectrophotometrically. After having constructedE1-deleted vectors, it was determined that HEK 293 cells (which expresshuman adenovirus serotype 5 E1 functions) trans-complement the E1deletions of the novel viral vectors and allow for the production ofhigh titer stocks. Examples of virus yields for a few of theserecombinant viruses are shown in the table below.

[0265] The transgenes for these vectors, β-galactosidase (LacZ), greenfluorescent protein (GFP), alpha-1-anti-trypsin (A1AT), ebolaglycoprotein (ebo), a soluble ebola glycoprotein variant lacking thetransmembrane and cytoplasmic domains (sEbo), and three deletion mutantsof the ebola glycoprotein (EboΔ2, EboΔ3, and EboΔ4), were expressed bythe cytomegalovirus promoter (CMV). In the following table, ND indicatesthat the study has not yet been done. Viral backbone/Vector yield (Viralparticles × 10¹³) Transgene AdHu5 AdC7 AdC68 AdC6 CMVLacZ 1.5 1.4 3.36.1 CMVGFP 2.5 3.6 8 10 CMVA1AT 3.7 6 10 ND CMVEbo 1.1 4.3 ND ND CMVsEbo4.9 5.4 ND ND CMVEboΔ2 1 9.3 ND ND CMVEboΔ3 0.8 9.5 ND ND CMVEboΔ4 1.46.2 ND ND

[0266] The ability of human adenovirus E1 to trans-complement theE1-deleted chimpanzee viruses of the invention is highly advantageous,as it permits the production of E1-deleted chimpanzee adenoviral vectorsof the invention, while reducing or eliminating the risk of homologousrecombination due to the differences in sequences between human Ad andthe chimpanzee adenoviruses described herein.

EXAMPLE 18 Serological Studies of Pan 5, 6, and 7 Viruses

[0267] Because of the differences in the hexon hypervariable region, itwas anticipated that the C5, C6, and C7 viruses would be serologicallydistinct from human adenoviruses, including AdHu4.

[0268] 1. Cross-Reactivity of Wild-Type Viruses

[0269] For screening of wild-type viruses in order to make adetermination of antibody cross-reactivity, the replication competentviruses were used and inhibition of cytopathic effects (CPE) wasmeasured. Briefly, preparations of adenoviruses (Adhu5, Pan-5, Pan-6,Pan-7 and AdC68) stored at 5×10¹² particles/ml were diluted 1/600 forthe assays. This concentration of virus was selected since it results in100% CPE within 48 hours in the absence of neutralization. Prior toadding the virus to 293 cells (4×10⁴ cells/well in a 96 well dish), 1:20dilutions of sera were added. The assay is read as the presence orabsence of CPE; full neutralization would read as no cytopathic effect.The results are summarized in the Table below. The fact that 9/36 humansera neutralized Adhu5 induced CPE is consistent with previous estimatesof neutralizing antibodies in the human population. The numbers indicatethe total individuals who showed neutralization (numerator) versus thetotal number screened (denominator). ND=not determined.

[0270] Neutralization by 1/20 diln of serum Human Rhesus Chimpanzee (N =36) (N = 52) (N = 20) Adhu5 9/36 ND ND AdC68 1/36 0/52 12/20 Pan 5 0/360/52 10/20 Pan 6 0/36 0/52  9/20 Pan 7 0/36 0/52 12/20

[0271] Of all human sera screened, 35/36 were negative forneutralization to AdC68 while 36/36 were negative for neutralization toPan-5, Pan-6 and Pan-7. Of 52 rhesus monkeys screened, none showedneutralization to any chimpanzee adenovirus; rhesus monkey is thepreferred pre-clinical model for evaluating HIV vaccines. Between 9 to12 out of 20 chimpanzees had substantial neutralization to one oranother of the chimpanzee adenoviruses consistent with the fact theseare indeed endemic chimpanzee-specific pathogens. Interestingly, thereare chimpanzees with neutralizing antibodies only to Pan-5, Pan-6 orAdC68 supporting the hypothesis that several of these chimpanzeeadenoviral vectors will not cross neutralize each other and are distinctserotypes.

[0272] The same assay was carried out for 20 chimpanzee serum samples.Fifty percent (50%) of the samples reacted serologically, in differentdegrees to Pan5; 40% to Pan6; 55% to Pan7 and 60% to C68. Among thepositive serum samples, one of them had strong neutralizing activity toall four chimp viruses.

[0273] 2. Cross-Neutralization with Recombinant Viruses

[0274] High-titer polyclonal antibodies were obtained to each of thesimian adenoviruses in order to more precisely gauge the degree ofcross-neutralization among the different serotypes. This was done byintramuscular immunization of rabbits using a recombinant viruscontaining GFP based on previously the described C68 chimpanzeeadenovirus as an adjuvant. The serum was then used to assay forneutralizing activity against each of the three chimpanzee adenovirusesof the invention, AdC5, AdC6 and AdC7. A rabbit was injected with 5×10¹²viral particle per kg of C68CMVGFP vector intramuscularly and boosted 5weeks later using the same dose. A bleed collected at the 9 week timepoint revealed extremely potent neutralizing activity against C68 aswell as Pan-5 and Pan-7 but not against Pan-6 (see Table below),indicating that the administration of a C68 (or Pan-5 and Pan-7) basedvaccine could be effectively followed by a boost using a vector based onPan-6. However, it has been found that this level of inter-relatednessdoes not necessarily prevent with re-administration in a setting whereantiviral antibody titers were not as high as was achieved in thisrabbit. In the following table, + indicates 33% CPE; ++ indicates 66%CPE; +++ indicates 100% CPE. Infection on 293 cells with virus: C68Serum Pan5 Pan6 Pan7 Pan9(C68) GFP Dilution − +++ − − − 1/20 − +++ − − −1/40 − +++ − − − 1/80 − +++ − − − 1/160 − +++ − − − 1/320 − +++ − − −1/640 − +++ − − − 1/1,280 − +++ − − − 1/2,560 − +++ − − − 1/5,120 + +++− − − 1/10,240 + +++ ++ − − 1/20,480 ++ +++ +++ − − 1/40,960 ++ ++++++ + + 1/81,920 +++ +++ +++ ++ ++ 1/163,840 +++ +++ +++ +++ +++1/327,680 +++ +++ +++ +++ +++ 1/665,360 +++ +++ +++ +++ +++ 1/1,310,720+++ +++ +++ +++ +++ 1/2,621,440

[0275] 3. Quantitative Assay for Detection of Neutralizing Antibody

[0276] The result was validated by a more quantitative-based assay fordetecting neutralizing antibody, which is based on transduction of a GFPvector. Briefly, groups of C57BL/6 mice were immunized intramuscularlyor intravenously with 5.0×10¹⁰ particles/ml Pan5, Pan6, Pan7 or C68.Sera from day 28 bleeds were tested for cross-neutralizing activityagainst C68CMVEGFP at dilutions of 1/20 and 1/80. In summary, when apharmaceutical preparation of human immunoglobulin was tested forserological reactions to Pan 5, 6, and 7, and C68, some low levels ofneutralizing activities against Pan 7 and C68 were detected. Noneutralizing activity against Pan5 or Pan6 was detected. Serum samplesfrom 36 human subjects were run for the same assay. Serum samples weretested at a 1/20 dilution. The results indicated that only oneindividual has clear neutralizing activity to C68. No neutralizingactivity to Pan5, Pan6 or Pan7 was detected.

[0277] 4. In Vitro Cross-Neutralization

[0278] Cross-neutralization of the simian adenoviruses by high-titerrabbit polyclonal antibodies raised against each of the adenovirusesPan-5, Pan-6, Pan-7, and C68 was tested.

[0279] Rabbits were immunized with intra-muscular injections of 10¹³particles of each of the chimpanzee adenoviruses and boosted 40 dayslater with the same dose with incomplete Freund's adjuvant. Sera wereanalyzed or the presence of neutralizing antibodies by incubating serialtwo-fold dilutions with 109 genome copies of each of the appropriatechimpanzee adenovirus vector expressing GFP and testing for theattenuation of GFP expression when applied to 293 cells. The serumdilution which produced a 50% reduction of GFP expression was scored asthe neutralizing antibody titer against that particular virus.

[0280] The results are shown in the Table. The data are consistent withthe expectation from sequence analysis of the hexon amino-acidsequences, which indicated that Ad Pan-6 was likely to be the mostserologically distinct compared to the other chimpanzee adenoviruses.Serum from rabbit immunized Infection of 293 cells with 10⁹ genomecopies of with: Ad Pan-5 Ad Pan-6 Ad Pan-7 Ad C68 Ad Pan-5 1/5120 <1/20 1/2560  1/2560 Ad Pan-6 No  1/20,480 <1/20 <1/20 neutralization AdPan-7 1/2560  1/160  1/163,840  1/2560 Ad C68 No <1/20 <1/20  1/5120neutralization

[0281] In order to determine whether antibodies cross-reacting with thesimian adenoviruses were likely to be of low prevalence in humans,simian adenoviruses SV1, SV39, and SV25 were tested for their ability towithstand neutralization when incubated with commercially availablepooled human immunoglobulins (Ig). The same assay was also performedwith Adhu5 and the chimpanzee adenoviruses Pan-5, Pan-6, Pan-7, and C68.In a further study, sera from mice has been immunized with one of thechimpanzee adenoviruses C5, C6, C7, and C68 and their ability tocross-neutralize the simian adenoviruses SV-15, SV-23, SA-17, and BaboonAdenovirus has been tested. No cross-reactivity was observed in anycase.

EXAMPLE 19 Generation of Recombinant E1-Deleted Pan5 Vector

[0282] A modified pX plasmid was prepared by destroying the FspI site inthe bla gene region of pX (Clontech) by site-directed mutagenesis. Theresulting modified plasmid, termed pX′, is a circular plasmid of 3000 bpwhich contains an fl ori and an ampicillin resistance gene (AmpR-cds).

[0283] A. Production of Pan-5 Adenovirus Plasmid

[0284] A polylinker for sequential cloning of the Pan5 DNA fragmentsinto pX′ is created. The polylinker is substituted for the existing pX′polylinker following digestion with Mlui and EcoRI. The blunt-Fseifragment of the Pan 5 is inserted into the SmaI and FseI sites of thepolylinker. This fragment contains the 5′ end of the adenoviral genome(bp 1 to 3606, SEQ ID NO:1). The SnaBI-Fspl fragment of Pan 5 (bp 455 to3484, SEQ ID NO:1) is replaced with a short sequence flanked by I-Ceuand PI-Sce sites from pShuttle (Clontech), to eliminate the E1 region ofthe adenoviral genome. The EcoRI-blunt fragment of Pan5 (bp 28658 to36462, SEQ ID NO:1) is inserted into the EcoRI and EcoRV sites of thepolylinker (to provide the 3′ end of the adenoviral genome); theFseI-MluI fragment (bp 3606 to 15135, SEQ ID NO:1) is inserted into thepolylinker; and the MluI-EcoRI fragment is inserted into the polylinker(bp 15135 to 28658, SEQ ID NO:1). Optionally, a desired transgene isinserted into I-Ceul and PI-SceI sites of the newly created pX′Pan5ΔE1vector.

[0285] B. Alternative Method of Generating pX′Pan5ΔE1.

[0286] The initial plasmid pX is derived from pAdX adenovirus plasmidavailable from Clontech, as described above. Thereafter, a PacI-XhoIregion of pX′ was deleted and the blunt-ended Pan5 polylinker wasinserted into the FspI site to generate pX′PLNK (2994 bp). The5′end-FseI region of Pan 5 (bp 1-3607, SEQ ID NO:1) was inserted intoSmaI and FseI sites of pX′LNK to generate the pX′Pan5-5′ plasmid (6591bp). The SnaBi-NdeI region of pX′Pan5-5′ was excised and replaced withthe Ceu/Sce cassette, which had been PCR amplified from pRCS to createpX′Pan5-5′ΔE1 (4374 bp). Briefly, a sequence containing I-CeuI andPI-SceI rare cutter sites was PCR amplified from pRCS (3113bp). The 3′PCR primer was introduced an NdeI site into the PCR product.

[0287] To extend the Pan5 DNA in pX′Pan5-5′ΔE1 (4374 bp), the FseI-MluIregion of Pan 5 (bp 3607-15135, SEQ ID NO:1) is added, to createpX′Pan5-5′Mlu (15900 bp). The remaining MluI-3′ end of the Pan5 sequence(bp 15135-36462, SEQ ID NO:1) is added to the vector between the MluIand EcoRV sites of the vector polylinker to form pX′Pan5ΔE1 whichcontains the full-length Pan5 sequence containing a deletion in the E1region.

[0288] C. Generation of Recombinant Viruses

[0289] To generate the recombinant adenoviruses from pX′Pan566 E1, theplasmid is co-transfected with a helper expressing E1, or from anE1-expressing packaging cell line, such as 293 cell line or a cell lineprepared as described herein. The expression of E1 in the packaging cellpermits the replication and packaging of the Pan5ΔE1 into a virioncapsid. In another embodiment, the packaging cell transfected withpX′Pan5ΔE1 is transfected with an adenovirus vector as described abovebearing the transgene of interest. Homologous recombination occursbetween the helper and the plasmid, which permits theadenovirus-transgene sequences in the vector to be replicated andpackaged into virion capsids, resulting in the recombinant adenovirus.

[0290] Transfection is followed by an agar overlay for 2 weeks, afterwhich the viruses are plaqued, expanded and screened for expression ofthe transgene. Several additional rounds of plaque purification arefollowed by another expansion of the cultures. Finally the cells areharvested, a virus extract prepared and the recombinant chimpanzeeadenovirus containing the desired transgene is purified by buoyantdensity ultracentrifugation in a CsCl gradient or by alternative meansknown to those of skill in the art.

EXAMPLE 20 Generation of Recombinant E1-Deleted Pan6 Vector

[0291] A. Strategy for Construction of Pan-6 Adenoviral Plasmid

[0292] 1. Cloning of Terminal Fragments

[0293] Pan 6 virus is deproteinated by pronase and proteanase Ktreatment and phenol extraction. Synthetic 12 bp Pme I linkers areligated onto the viral DNA as described by Berkner and Sharp, NucleicAcids Research, 11: 6003 (1983). The viral DNA is then digested with XbaI to isolate a 5′ terminal fragment (6043 bp). The Ad6 XbaI 5′ fragmentis then ligated into pX link at Sma I and Xba I sites to formpX-AdPan6-0-16.5. The viral DNA with Pme I linkers is also digested withPac I to isolate the 6475 bp 3′ terminal fragment and cloned into pXlink at Pac I and Sma I sites, resulting in pXAdPan6-82-100.

[0294] 2. Deletion of E1 from the 5′ Clone

[0295] To delete E1 (m.u.1.2-9), the BsiWi-Xba I fragment inpX-AdPan6-0-16.5 is replaced with a PCR fragment spanning m.u.9-16.7fragment treated with BsiWi and Xba I, leading to pX-Ad-Pan6 m.u.0-1,9-16.5.

[0296] 3. Fusion of 5′ and 3′ Clones and to Create an Anchor Site toAccept the Middle Hind III Fragment

[0297] First, the 5′ clone, pX-Ad-Pan6 m.u.0-1, 9-16.5, is furtherexpanded by inserting the 2^(nd) Xba I fragment (4350 bp, m.u.16.5-28)from Pan 6 genome into the Xba I site in the pX-Ad-Pan6 m.u.0-1, 9-16.5.This construct is named pXAd-Pan6-mu 0-1, 9-28.

[0298] Second, the 3′ clone is also expanded by inserting the 15026 bpMlu I/Pac I fragment covering m.u.41-82 from Pan 6 genome into the MluI/Pac I sites of pXAdPan6-82-100, generating pXAdPan6-m.u.4 1-100.

[0299] Then, a 8167 bp Hind III/Eco 47III Pan 6 fragment is isolatedfrom pXAd-Pan6-mu 0-1, 9-28 and subcloned into pXAdPan6-m.u.41-100 atHind III and Xba I blunt sites. This 5′ and 3′ fusion clone is calledpXAdPan6mu0-1, 9-19.5, 64-100.

[0300] 4. Drop of the Middle Fragment of the Genome into the FusionClone

[0301] A 16335 bp Hind III fragment (m.u.19.5-64) from Pan 6 is insertedinto Hind III site of pXAdPan6mu0-1,9-19.5, 64-100 to form pXAdPan6-0-1,9-100.

[0302] 5. Introduction of a PKGFP selective marker into the finalconstruct for direct cloning the gene of interest and green/whiteselection of recombinant transformants.

[0303] A minigene cassette that expresses GFP under a lac promoter andis flanked with recognition sites of rare intron encoding restrictionenzymes, PI-Sce I and I-Ceu I, was isolated from pShuttle-pkGFP (bare)by Sap I and Dra III digestions followed by filling-in reaction. ThepShuttle-pkGFP (bare) plasmid is 4126 bp in length, and contains aColE1-Ori, a kanamycin resistance gene, plac, a LacZ promoter-GFPmut3-Icds (Clontech), and a GFPmut3-1 cds (Clontech). This cassette issubcloned into Srf I cut and blunted pXAdPan6-0-1, 9-100. This finalconstruct is called pX-Pan6-pkGFP mu.0-1,9-100, which is useful forgenerating recombinant E1-deleted Pan 6 molecular clones carrying genesof interest by direct ligation and green/white selection in combinationwith the generic pShuttlepkGFP vectors.

[0304] B. Alternative Strategy for Generation of Pan-6 Plasmid

[0305] 1. Cloning of 5′ Terminal Fragment

[0306] The Pan 6 virus is deproteinated by pronase and proteanase Ktreatment and phenol extraction as described above and synthetic 12 bpPme I linkers are ligated onto the viral DNA as described. The AdPan6 5′XbaI fragment is isolated and ligated into pX to form pX-AdPan6-0-16.5(9022 bp) as described in Part A above.

[0307] 2. Deletion of E1 from the 5′ Clone

[0308] To delete E1 (m.u. 1.2-9), pX-AdPan6-0-16.5 is digested withSnaBI and NdeI to remove the regions encoding the E1a and E1b proteins(3442-6310 bp). This vector is subsequently digested with BsiWI inpreparation for blunting with the minigene cassette carrying a selectivemarker.

[0309] 3. Introduction of a Selective Marker

[0310] A minigene cassette that expressed GFP under a lac promoter andwhich is flanked with recognition sites of rare intron encodingrestriction enzymes, PI-XceI and I-Ceul, was isolated frompShuttle-pkGFP as described above. The DraIII-SapI fragment is thenligated with the digested pX-AdPan6-0-16.5 to form pX-AdPan6 MU0-16.5ΔE1 (7749 bp).

[0311] 4. Extension of Pan-6 Adenoviral Sequences

[0312] pX-AdPan6 MU 0-16.5ΔE1 was subjected to XbaI digestion to permitinsertion of an Xbal-RsrII linker. An XbaI/RsrII digestion fragment fromthe AdPan6 genome was isolated (mu 28-100, 26240 bp) and ligated intothe Xba/RsrII-digested pX-AdPan6 MU 0-16.5ΔE1 to provide pX-AdPan6 MU0-1, 9-16.5, 28-100. A second XbaI fragment from the Pan6 genome (mu16.5-28, 4350 bp) is then ligated into this plasmid to form pX-AdPan6 MU0-1, 9-100 (38551 bp).

[0313] C. Generation of Recombinant Adenoviruses

[0314] To generate the recombinant adenoviruses from a E1-deleted Pan6plasmid prepared as described in Parts A or b, the plasmid isco-transfected with a helper expressing E1, or from an E1-expressingpackaging cell line, such as 293 cell line or a cell line prepared asdescribed herein. The expression of E1 in the packaging cell permits thereplication and packaging of the Pan6-pkGFP mu.0-1, 9-100 into a virioncapsid. Alternatively, the packaging cell transfected with pX-Pan6-pkGFPmu.0-1, 9-100 is transfected with an adenovirus vector as describedabove bearing another transgene of interest.

EXAMPLE 2 Generation of Recombinant E1-Deleted Pan7 Vector

[0315] A. Generation of Pan7 Plasmids

[0316] A synthetic linker containing the restriction sitesPacI-SmaI-FseI-MluI-EcoRV-PacI was cloned into pBR322 that was cut withEcoRI and NdeI. The left end (bp1 to 3618) of Ad Pan7 was cloned intothe linker between the SmaI and FseI sites. The adenovirus E1 was thenexcised from the cloned left end by cutting with SnaBI and NdeI andinserting an I-CeuI-GFP-PI-SceI cassette from pShuttle (Clontech) in itsplace. The resulting plasmid was cut with FseI and MluI and Ad Pan7fragment FseI (bp 3618) to MluI (bp 155114 was inserted to extend theleft end. The construct (pPan7pGFP) was completed by inserting the 21421bp Ad Pan7 right end fragment from the MluI site (bp 15114) into theabove plasmid between MluI and EcoRV to generate a complete molecularclone of E1 deleted adenovirus Pan7 suitable for the generation ofrecombinant adenoviruses. Optionally, a desired transgene is insertedinto the I-Ceul and PI-SceI sites of the newly created pPan7 vectorplasmid.

[0317] B. Construction of E1-Deleted Pan 7 Viral Vectors

[0318] To generate the recombinant adenoviruses from pPan7ΔE1, theplasmid is co-transfected with a helper expressing E1, or from anE1-expressing packaging cell line, such as 293 cell line or a cell lineprepared as described herein. The expression of E1 in the packaging cellpermits the replication and packaging of the Pan7ΔE1 into a virioncapsid. In another embodiment, the packaging cell transfected withpX′Pan7ΔE1 is transfected with an adenovirus vector as described abovebearing the transgene of interest. Homologous recombination occursbetween the helper and the plasmid, which permits theadenovirus-transgene sequences in the vector to be replicated andpackaged into virion capsids, resulting in the recombinant adenovirus.Transfection and purification is as described above.

EXAMPLE 22 Generation of Plasmid Vectors Expressing the E1 Genes

[0319] Plasmid vectors are constructed which encode the Pan5 E1 regiongene, and these plasmids are used to generate stable cell linesexpressing viral E1 proteins.

[0320] The E1 region of Pan5 is cloned into pX′, essentially asdescribed in Example 19 above, prior to replacement of this region withthe fragment from pShuttle (Clontech). The expression plasmid containsthe Pan5 adenoviral genome sequence spanning at least bp 1 to 3959 inthe Pan5 genomic sequence. Thus, the expression plasmid contains thesequence encoding E1a and E1b of chimpanzee Ad Pan5 under the control ofa heterologous promoter. Similar expression plasmids can be generatedusing the Ad Pan6 and AdPan 7 E1 regions, identified in the tablesabove.

EXAMPLE 23 Generation of Cell Lines Expressing Chimpanzee Adenovirus E1Proteins

[0321] Cell lines expressing viral E1 proteins are generated bytransfecting HeLa (ATCC Acc. No. CCL2) with the plasmid of Example 21.These cell lines are useful for the production of E1-deleted recombinantchimpanzee adenoviruses by co-transfection of genomic viral DNA and theexpression plasmids described above. Transfection of these cell lines,as well as isolation and purification of recombinant chimpanzeeadenoviruses therefrom are performed by methods conventional for otheradenoviruses, i.e., human adenoviruses [see, e.g., Horwitz, cited aboveand other standard texts].

[0322] A. Cell Lines Expressing Pan5 E1 Proteins

[0323] HeLa cells in 10 cm dishes are transfected with 10 μg of pX-Pan51-E1 DNA using a Cellphect™ kit (Pharmacia, Uppsala, Sweden) andfollowing the manufacturer's protocol. 22 hours post-transfection, thecells are subjected to a three minute glycerol shock (15% glycerol inHepes Buffered Saline, pH 7.5) washed once in DMEM (HeLa) or F12K (A549;Life Technologies, Inc., Grand Island, N.Y.) media supplemented with 10%FCS, 1% Pen-Strep, then incubated for six hours at 37° C. in the abovedescribed media. The transfected cells are then split into duplicate15cm plates at ratios of 1:20, 1:40, 1:80, 1:160, and 1:320. Followingincubation at 37° C. overnight, the media is supplemented with G418(Life Technologies, Inc.) at a concentration of 1 μg/ml. The media isreplaced every 5 days and clones are isolated 20 days post-transfection.

[0324] HeLa E1 cell clones are isolated and assayed for their ability toaugment adeno-associated virus (AAV) infection and expression ofrecombinant LacZ protein as described below.

[0325] B. AAV Augmentation Assay for Screening E1 Expressing Cell Lines

[0326] AAV requires adenovirus-encoded proteins in order to complete itslife cycle. The adenoviral E1 proteins as well as the E4 region-encodedORF6 protein are necessary for the augmentation of AAV infection. Anassay for E1 expression based on AAV augmentation is used. Briefly, themethod for identifying adenoviral E1-expressing cells comprises thesteps of infecting in separate cultures a putative adenovirusE1-expressing cell and a cell containing no adenovirus sequence, withboth an adeno-associated virus (AAV) expressing a marker gene and an AAVexpressing the ORF6 of the E4 gene of human adenovirus, for a suitabletime. The marker gene activity in the resulting cells is measured andthose cells with significantly greater measurable marker activity thanthe control cells are selected as confirmed E1-expressing cells. In thefollowing experiment, the marker gene is a lacZ gene and the markeractivity is the appearance of blue stain.

[0327] For example, the cell lines described above, as well asuntransfected control cells (HeLa) are infected with 100 genomes percell of an AAV vector bearing a marker gene, e.g., AV.LacZ [K. Fisher etal., J. Virol., 70:520 (1996)] and an AAV vector expressing the ORF6region of human 5 (AV.orf6). The DNA sequence of the plasmid generates anovel recombinant adeno-associated virus (rAAV) containing the LacZtransgene and the Ad E4 ORF 6, which is an open reading frame whoseexpression product facilitates single-stranded (ss) to double-stranded(ds) conversion of rAAV genomic DNA. These vectors are incubated inmedium containing 2% FCS and 1% Pen-Strep at 37° C. for 4 hours, atwhich point an equal volume of medium containing 10% FCS is added. Itshould be understood by one of skill in the art that any marker gene (orreporter gene) may be employed in the first AAV vector of this assay,e.g., alkaline phosphatase, luciferase, and others. An antibody-enzymeassay can also be used to quantitate levels of antigen, where the markerexpresses an antigen. The assay is not limited by the identity of themarker gene. Twenty to twenty-four hours post-infection, the cells arestained for LacZ activity using standard methods. After 4 hours thecells are observed microscopically and cell lines with significantlymore blue cells than the A549 or HeLa cell controls are scored aspositive.

EXAMPLE 24 Delivery of Transgene to Host Cell

[0328] The resulting recombinant chimpanzee adenovirus described inExample 19, 20 or 21 above is then employed to deliver the transgene toa mammalian, preferably human, cell. For example, following purificationof the recombinant virus, human embryonic kidney 293 cells are infectedat an MOI of 50 particles per cell. GFP expression was documented 24hours post-infection.

[0329] A. Gene Transfer in Mouse Models via Pan-6, Pan-7, and Pan-9Vectors

[0330] Gene transfer efficiencies and toxicological profile ofrecombinant chimpanzee adenoviruses were compared in mouse liverdirected gene transfer, mouse lung directed gene transfer, and mousemuscle directed gene transfer.

[0331] E1-deleted adenoviral vectors containing LacZ under the controlof the CMV promoter were constructed using the techniques herein forhuman Ad5, chimpanzee Pan 6, chimpanzee Pan 7 and chimpanzee Pan 9(C68). The vectors were delivered to immune-deficient NCR nude mice (80for each study) as follows. For the liver study, 100 μl (1×10¹¹particles) were injected into the tail vein. For the lung study, 50 μl(5×10¹⁰ particles) were delivered intratracheally. For the muscle study,25 μl (5×10¹⁰ particles) were injected into tibialis anterior. The micewere sacrificed on days 3, 7, 14 and 28 post-vector injection (5 animalsper group at each time point). At each necropsy, the liver/lung/muscletissue was harvested and prepared for cryoblocks and paraffin embedding.The cryoblocks were sectioned for X-gal staining and the paraffinsections are H&E stained for histopathic analysis. At each time point,terminal bleeding was performed. Serum samples were subjected to liverfunction tests.

[0332] It was observed in this experiment the chimpanzee adenovirusesPan-6, Pan-7, and Pan-9 were less efficient than huAd5 in gene transferto the liver and to the lung. However, this may be desirable in certaincircumstances, to reduce liver toxicity observed for huAd5. The genetransfer efficiency in muscle varied less between serotypes.

[0333] B. Mouse Study to Feasibility of Re-Administration of AdenovirusVectors by Serotype Switching Between Adhu5, Pan-6, Pan- 7, and Pan-9Vectors

[0334] Mice were administered (C57/B16; 4/group) LacZ vectors based onhuAd5, Pan-6, Pan-7, and Pan-9 (H5.040CMVLacZ, Pan6.000CMVLacZ, 5Pan7.000CMVLacZ, Pan9.000CMVLacZ; 10¹¹ particles/injection) by tailvein. Thirty days later the mice were re-administered adenovirus vectorsexpressing al-antitrypsin (H5.040CMVhA1AT, Pan6.000CMVhA1AT, 1×10¹¹particles, Pan7.000CMVhA1AT, Pan9.000CMVhAIAT, 10¹¹particles/injection).Successful transduction by the re-administered vector is monitored bymeasuring serum α1-antitrypsin on days 3 and 7, followingre-administration.

[0335] The ability of adenovirus vectors based on huAd5, Pan-6, Pan-7,and Pan-9 respectively to transduce the livers of mice in the presenceof neutralizing antibodies to the other serotypes was determined. Theresults are tabulated here. 1^(st) injection 2^(nd) injectionCross-neutralization Adhu5 Adhu5 Yes (+ve control) Pan-6 No Pan-7 NoPan-9 (C68) No Pan-6 Adhu5 No Pan-6 Yes (+ve control) Pan-7 Yes Pan-9(C68) No Pan-7 Adhu5 No Pan-6 Yes Pan-7 Yes (+ve control) Pan-9 (C68)Yes Pan-9 (C68) Adhu5 No Pan-6 No Pan-7 Yes Pan-9 (C68) Yes (+vecontrol)

[0336] C. Ability of Vectors to Transduce Murine Liver in the Presenceof Neutralizing Antibodies to Other Serotypes.

[0337] Thus, immunization with huAd5 does not prevent re-administrationwith either of the chimpanzee adenovirus vectors Pan-6, Pan-7, or Pan-9(C68). This experiment also appears to indicate that Pan-7 is betweenPan-6 and Pan-9 in the spectrum of antigenic relatedness andcross-reacts with both; however Pan-6 and Pan-9 do not neutralize eachother. This is a surprising result based on homology comparisons, whichindicates that Pan-6 is quite distinct from Pan-7 and Pan-9. Evaluationof antisera generated against Pan-9 indicated no cross-neutralizationagainst Pan-6 but some neutralization against Pan-7, arguing that Pan-6is distinct from the others.

EXAMPLE 25 Generation of Recombinant E1-Deleted SV-25 Vector

[0338] A plasmid was constructed containing the complete SV-25 genomeexcept for an engineered E1 deletion. At the site of the E1 deletionrecognition sites for the restriction enzymes I-CeuI and PI-SceI whichwould allow insertion of transgene from a shuttle plasmid where thetransgene expression cassette is flanked by these two enzyme recognitionsites were inserted.

[0339] A synthetic linker containing the restriction sitesSwaI-SnaBI-SpeI-AflII-EcoRV-SwaI was cloned into pBR322 that was cutwith EcoRI and NdeI. This was done by annealing together two syntheticoligomers SV25T (5′-AAT TTA AAT ACG TAG CGC ACT AGT CGC GCT AAG CGC GGATAT CAT TTA AA-3′, SEQ ID NO: 38) and SV25B (5′-TAT TTA AAT GAT ATC CGCGCT TAA GCG CGA CTA GTG CGC TAC GTA TTT A-3′, SEQ ID NO:39) andinserting it into pBR322 digested with EcoRI and NdeI. The left end (bp1to 1057, SEQ ID NO:29) of Ad SV25 was cloned into the above linkerbetween the SnaBI and SpeI sites. The right end (bp28059 to 31042, SEQID NO: 29) of Ad SV25 was cloned into the linker between the AflII andEcoRV sites. The adenovirus E1 was then excised between the EcoRI site(bp 547) to XhoI (bp 2031) from the cloned left end as follows. A PCRgenerated I-Ceul-PI-SceI cassette from pShuttle (Clontech) was insertedbetween the EcoRI and SpeI sites. The 10154 bp XhoI fragment of Ad SV-25(bp2031 to 12185, SEQ ID NO:29) was then inserted into the Spel site.The resulting plasmid was digested with HindIII and the construct(pSV25) was completed by inserting the 18344 bp Ad SV-25 HindIIIfragment (bpl 1984 to 30328, SEQ ID NO:29) to generate a completemolecular clone of E1 deleted adenovirus SV25 suitable for thegeneration of recombinant adenoviruses. Optionally, a desired transgeneis inserted into the I-Ceul and PI-SceI sites of the newly created pSV25vector plasmid.

[0340] To generate an AdSV25 carrying a marker gene, a GFP (greenfluorescent protein) expression cassette previously cloned in theplasmid pShuttle (Clontech) was excised with the restriction enzymesI-Ceul and PI-SceI and ligated into pSV25 (or another of the Ad chimpplasmids described herein) digested with the same enzymes. The resultingplasmid (pSV25GFP) was digested with SwaI to separate the bacterialplasmid backbone and transfected into the E1 complementing cell line HEK293. About 10 days later, a cytopathic effect was observed indicatingthe presence of replicative virus. The successful generation of an AdSV25 based adenoviral vector expressing GFP was confirmed by applyingthe supernatant from the transfected culture on to fresh cell cultures.The presence of secondarily infected cells was determined by observationof green fluorescence in a population of the cells.

EXAMPLE 26 Construction of E3 Deleted Pan-5, Pan-6, Pan-7 and C68Vectors

[0341] In order to enhance the cloning capacity of the adenoviralvectors, the E3 region can be deleted because this region encodes genesthat are not required for the propagation of the virus in culture.Towards this end, E3-deleted versions of Pan-5, Pan-6, Pan-7, and C68have been made (a 3.5 kb Nru-AvrII fragment containing E31-9 isdeleted).

[0342] A. E3 Deleted Pan5 Based Vector

[0343] E1-deleted pPan5-pkGFP plasmid was treated with Avr IIendonuclease to isolate a 5.8 kb fragment containing the E3 region andre-circulate pPan5-pkGFP with Avr II deletion to form constructpPan5-pkGFP-E3-Avr II. Subsequently, the 5.8 kb Avr II fragment wassubcloned into pSL-Pan5-E3-Avr II for a further deletion of E3 region byNru I digestion. This led to a plasmid pSL-Pan5-E3-deletion. The finalconstruct pPan5-E3-pkGFP was produced by removing a 4.3 kb Avr II/Spe Ifragment from pSL-Pan5-E3-deletion plasmid and inserting intopPan5-pkGFP-E3-Avr II at Avr II site. In this final construct, a 3.1 kbdeletion in E3 region was accomplished.

[0344] B. E3 Deletion in Pan6 Based Vector

[0345] E1-deleted pPan6- pkGFP molecular clone was digested with Sbf Iand Not I to isolate 19.3 kb fragment and ligated back at Sbf I site.The resulting construct pPan6-Sbf I-E3 was treated with Eco 47 III andSwa I, generating pPan6-E3. Finally, 21 kb Sbf I fragment from Sbf Idigestion of pPan6- pkGFP was subcloned into pPan6-E3 to createpPan6-E3-pkGFP with a 4 kb deletion in E3.

[0346] C. E3 Deleted Pan 7 and Pan9 Vectors

[0347] The same strategy was used to achieve E3 deletions in bothvectors. First, a 5.8 kb Avr II fragment spanning the E3 region wassubcloned pSL-1180, followed by deletion of E3 by Nru I digestion. Theresulting plasmids were treated with Spe I and Avr II to obtain 4.4 kbfragments and clone into pPan7-pkGFP and pPan9-pkGFP at Avr II sites toreplace the original E3 containing Avr II fragments, respectively. Thefinal pPan7-E3- pkGFP and pPan9-E3-pkGFP constructs have 3.5 kbE3-deletions.

EXAMPLE 27 Construction of E3-and E4-Deleted Pan-7 Vector

[0348] Although the deletion of the E1 region of adenoviruses (firstgeneration adenovirus vectors) renders them replication-incompetent,expression of the adenoviral vector backbone genes is not fullyabolished. Deletion of the E4 region considerably attenuates thisresidual gene expression and may confer a safety advantage. AnE4-deleted Pan-7 vector containing a 2.5 kb deletion (a PvuII-AgeIfragment containing E40RF1-ORF7 is deleted) has been constructed. Hightiter stocks of this virus were generated using a HEK 293-based cellline, which in addition to E1, expresses an essential E4 gene (orf 6).

[0349] 1. E4 Deletion in the Molecular Clone of Pan7

[0350] A 19 kb Xba I fragment was deleted from pPan7-pkGFP to createpPan7-Xba I from which a 2.5 kb E4 fragment was deleted by Age I and PvuII partial digestion, resulting in pPan7-Xba I-E4. pPan7-E4-pkGFPplasmid was generated from pPan7-Xba I-E4 in two sequential cloningsteps, adding 19 kb Xba I and 15 kb I-Ceu I/Mlu I fragments, both ofwhich came from pPan7-pkGFP construct.

[0351] 2. Introduction of E3 and E4 Deletions in Pan9 Vector

[0352] An 11 kb plasmid, pPan9-EcoRI, containing E4 region was createdby retrieving 11 kb EcoRI fragment from pPan9 pkGFP after EcoRIdigestion and self-ligation. E4 region was deleted from this constructby Age I digestion/filled in and Pvu II partial digestion andslef-ligation to generate pPan9-EcoR I-E4. A 23 kb EcoR I fragment wasisolated from pPan9-pkGFP and inserted into pPan9-EcoR I-E4 at EcoR Isite, followed by adding 5.8 kb Avr II fragment from pPan9-pkGFP, toform the final product pPan9-E3-E4-pkGF. Compared to the genome size ofwild type Pan9, this E1-E3-E4-deleted vector could have a transgenecapacity up to 8 kb.

[0353] 3. Introduction of Minigene Cassettes with Genes of InterestIncluding Reporter Genes, Glyco- and Nuclear Proteins of Ebo IntoMolecular Clones of Pan Vectors

[0354] A highly efficient direct cloning and green/white selectionprocedure was employed for creating molecular clones of recombinantviruses. Briefly, genes of interest were cloned into pShuttlepkGFP byscreening white colonies for recombinants. Subsequently, the minigenecassettes were transferred into chimpanzee adenovirus backbone plasmids,pPanX-pkGFP with various deletions, easily by swapping with pkGFPcassette at I-Ceu I and PI-Sce I sites and screening a few whitecolonies for correct recombinants.

[0355] 4. Rescue of Molecular Clones of Pan Vectors with MultipleDeletions in Early Regions and Virus Propagation

[0356] For rescue of E1-E3-deleted molecular clones of chimpanzeeadenovirus vectors, the clones were linearized with appropriaterestriction enzymes and transfected into regular 293 cells. Once a fullcytopathic effect (CPE) observed in the transfected cells, crude lysatewas harvested and expanded in 293 cells to large-scale infections. Theviruses were purified by CsCl sedimentation method.

[0357] For E1-E4 and E1-E3-E4-deleted Pan vectors, 10-3 cells, a293-based E1-E4-complementing cell line, were used for rescue andpropagation of vectors. E4 ORF6 gene expression in 10-3 cells wasinduced by addition of 150 μM ZnSO₄to the culture medium.

EXAMPLE 28 Vaccination with Adenovirus Vectors Expressing Wild Type andVariant EboZ GP

[0358] AdHu5 or AdC7 vectors expressing Ebola envelope chimeras wereproduced for in vivo immunization experiments in C57BL/6 mice.Recombinant viruses with different viral backbones were created bymolecular cloning method in which the minigene cassettes were insertedinto the place of E1-deletions. The molecular clones of all recombinantviruses were rescued and grown up in 293 cells for large-scalepurification using CsCl sedimentation method. Five EboZ variants encodedby AdHu5 or AdPan7 (C7) were selected and produced to evaluate theirrelative immunogenicity following an intramuscular Ad injection. The wtEbo, a soluble Ebo variant, EboΔ1, EboΔ2, EboΔ3, EboΔ4, EboΔ5S, EboΔ6S,EboΔ7S and EboΔ8S were evaluated in the initial vaccine studies. For thedata summarized in the following table, the number of viral particles(per ml or total) produced and amplified from infected 293 cells wasestablished by spectrophotometry reading. TABLE Production of Adhu5 orAdC7 Adenoviral vector encoding EboZ variant. HuAd5 AdC7 Total TotalTiter yield Titer yield Gene (VP × 10¹²/ml) (VP × 10¹²) (VP × 10¹²/ml)(VP × 10¹²) Ebo wt 2.6 12 4.3 43 EboS 4.9 49 4.6 55 EboΔ2 2.1 9 5.8 93EboΔ3 1.7 8 5.3 95 EboΔ4 3 12 4.1 62

[0359] Vector was administered intramuscularly (10¹¹ genome copies/cell)in C57BL/6 mice and the presence of virus neutralizing antibody (VNAOwas evaluated 28 days later as a first measure of an immune responsegenerated against the Ebola envelope glycoprotein. VNA is defined hereas serum antibody able to inhibit transduction of HeLa cells mediated byHIV-based vector pseudotyped with the wild-type Ebola envelope.

[0360] VNA to the EboZ pseudotypes was detected with AdPan7 (C7)yielding higher titers than AdHu5. The EboZΔ3 elicited the highest VNAin terms of the transgene targets. For the data summarized in thefollowing table, neutralizing antibody titers to HIV-EboZ-GFPpseudotypes (reciprocal dilution) are provided (N=5 animals/group). VNATiters EboZ wildtype EboZs EboZΔ3 AdHu5 12 16 12 AdC7 44 12 140

EXAMPLE 29 Pan7-Mediated Expression of Ebola Proteins

[0361] Mouse studies to evaluate Pan-7 vectors expressing Ebola envelopeproteins and the Ebola nuclear antigen have been initiated. These aredirected towards evaluation of neutralizing antibodies in C57B1/6 miceinjected intramuscularly (IM) with Adhu5 or Pan-7 expressing each of 4Ebola env constructs.

[0362] A. Evaluation of CTL From C57B1/6 Mice Injected IM With Adhu5 orPan-7 Expressing the Ebola Env Constructs.

[0363] 1. Challenge Experiment in Mice with Ebola Virus.

[0364] Neutralizing antibody (NAB) responses to the Ebola envelope wereanalyzed by looking at immunized mouse sera mediated neutralization of alentiviral (HIV) vector pseudotyped with the several constructs (eebo,NTD2, NTD3, NTD4) of the Ebola envelope glycoprotein. C57BL/6 or BALB/cmice received a single intramuscular injection of 5×10¹⁰ particles permouse of C7 (Ad Pan-7) encoding Ebola envelope variant. Neutralizingantibody was evaluated 30 days post-vaccination. Briefly, Ebola Zairepseudotyped HIV vector encoding for β-galactosidase (EboZ-HIV-LacZ) wasincubated for 2 hr at 37° C. with different dilution of heat inactivatedmouse serum. Following the incubation with serum, EboZ-HIV-LacZ was thenused to infect HeLa cells for 16 hr at 37° C. Infectivity was revealedby X-gal staining of transduced HeLa cells positive for β-galactosidase.Neutralizing titer represent the serum reciprocal dilution where a 50%decrease in the number of β-galactosidase positive blue cells wasobserved. Sera were collected 30 days post-immunization, which consistedin a single intramuscular (I.M.) administration of 5×10¹⁰particles/animal. Neutralizing antibody to Ebola pseudotyped HIV couldbe detected from all groups with antibody titers ranging from 20 forAd-EboZ (Adhu5 expressing EboZ), Ad-NTD3 (Adhu5 expressing NTD3) andC7-sEbo (Ad Pan-7 expressing soluble EboZ) to over 130 for C7-NTD3 (AdPan-7 expressing soluble NTD3) and C7-NTD4 (Ad Pan-7 expressing solubleNTD3). The same immunization strategy in BALB/c mice resulted in lowerneutralizing antibody titers for Ad- and C7-NTD2, and NTD4.

[0365] B. Cellular Immune Response

[0366] The cellular immune response to the Ebola envelope in C57BL/6mice was evaluated 8 days after a single I.M. administration of 5×10¹⁰particles of C7-LacZ or C7-Ebola envelope variant per animal. Mice werevaccinated I.M. with 5×10¹⁰ particles of C7 encoding LacZ or Ebolaenvelope variant. Splenic lymphocytes from immunized mice were collected8 days post vaccination and stimulated in vitro with feeder cells(splenic lymphocytes from untreated mice infected with human Adenovirusserotype 5 encoding for the wild-type Ebola envelope and irradiated).Standard 5-hr CTL assays were performed using ⁵¹Cr-labeled syngenic C57cells transfected with an expressor of EboZ.

[0367] A positive MHC-restricted cytotoxic T lymphocyte (CTL) responsewas observed from all AdPan-7 encoding for Ebola envelope variants witha higher response from NTD2, NTD3 or NTD4 immunized mice. Indeed,effector cells from C7 encoding Ebola envelope variant immunized micerecognized EboZ transfected target cells and gave recall CTL responsesup to 30% specific lysis. Less than 5% lysis was seen with effectorcells from naive or LacZ immunized control mice confirming that lysiswas specific for Ebola envelope antigens.

[0368] C. Protection Studies

[0369] The most direct means of evaluating C7 (Ad Pan-7) encoding forthe EboZ variants as a successful vaccine in mice was to assessprotection against weight loss and death following lethal challenge withmouse adapted Ebola Zaire virus. BALB/c mice were immunized with asingle dose of 5×10¹⁰ particles per animal as performed previously andvaccinated animals were challenged with 200 LD₅₀ of mouse adapted EbolaZaire 21 days later. All control mice (vehicle and C7-LacZ) died betweenday 5 to day 9 post-challenge. In contrast, all vaccinated mice but one,(from the C7-sEbo group), survived the challenge with Ebola Zaire. doseof C7-EboZ and C7-NTD4 completely protected immunized mice from illnessand death possibly due to a significant T cell mediated immunity.

[0370] All publications cited in this specification, and the sequencelisting, are incorporated herein by reference. While the invention hasbeen described with reference to particular embodiments, it will beappreciated that modifications can be made without departing from thespirit of the invention. Such modifications are intended to fall withinthe scope of the appended claims.

1 52 1 36462 DNA chimpanzee adenovirus serotype Pan5 CDS(13898)..(15490) L2 Penton 1 catcatcaat aatatacctc aaacttttgg tgcgcgttaatatgcaaatg aggtatttga 60 atttggggat gcggggcggt gattggctgc gggagcggcgaccgttaggg gcggggcggg 120 tgacgttttg atgacgtggc cgtgaggcgg agccggtttgcaagttctcg tgggaaaagt 180 gacgtcaaac gaggtgtggt ttgaacacgg aaatactcaattttcccgcg ctctctgaca 240 ggaaatgagg tgtttctggg cggatgcaag tgaaaacgggccattttcgc gcgaaaactg 300 aatgaggaag tgaaaatctg agtaattccg cgtttatggcagggaggagt atttgccgag 360 ggccgagtag actttgaccg attacgtggg ggtttcgattaccgtatttt tcacctaaat 420 ttccgcgtac ggtgtcaaag tccggtgttt ttacgtaggtgtcagctgat cgccagggta 480 tttaaacctg cgctctctag tcaagaggcc actcttgagtgccagcgagt agagttttct 540 cctccgcgcc gcgagtcaga tctacacttt gaaagatgaggcacctgaga gacctgcccg 600 gtaatgtttt cctggctact gggaacgaga ttctggaactggtggtggac gccatgatgg 660 gtgacgaccc tccggagccc cctaccccat ttgaagcgccttcgctgtac gatttgtatg 720 atctggaggt ggatgtgccc gagaacgacc ccaacgaggaggcggtgaat gatttgttta 780 gcgatgccgc gctgctggct gccgagcagg ctaatacggactctggctca gacagcgatt 840 cctctctcca taccccgaga cccggcagag gtgagaaaaagatccccgag cttaaagggg 900 aagagctcga cctgcgctgc tatgaggaat gcttgcctccgagcgatgat gaggaggacg 960 aggaggcgat tcgagctgca gcgaaccagg gagtgaaaacagcgagcgag ggctttagcc 1020 tggactgtcc tactctgccc ggacacggct gtaagtcttgtgaatttcat cgcatgaata 1080 ctggagataa gaatgtgatg tgtgccctgt gctatatgagagcttacaac cattgtgttt 1140 acagtaagtg tgattaactt tagctgggga ggcagagggtgactgggtgc tgactggttt 1200 atttatgtat atgtttttta tgtgtaggtc ccgtctctgacgtagatgag acccccacta 1260 cagagtgcat ttcatcaccc ccagaaattg gcgaggaaccgcccgaagat attattcata 1320 gaccagttgc agtgagagtc accgggcgta gagcagctgtggagagtttg gatgacttgc 1380 tacagggtgg ggatgaacct ttggacttgt gtacccggaaacgccccagg cactaagtgc 1440 cacacatgtg tgtttactta aggtgatgtc agtatttatagggtgtggag tgcaataaaa 1500 tccgtgttga ctttaagtgc gtggtttatg actcaggggtggggactgtg ggtatataag 1560 caggtgcaga cctgtgtggt cagttcagag caggactcatggagatctgg acagtcttgg 1620 aagactttca ccagactaga cagctgctag agaactcatcggagggagtc tcttacctgt 1680 ggagattctg cttcggtggg cctctagcta agctagtctatagggccaag caggattata 1740 aggatcaatt tgaggatatt ttgagagagt gtcctggtatttttgactct ctcaacttgg 1800 gccatcagtc tcactttaac cagagtattc tgagagcccttgacttttct actcctggca 1860 gaactaccgc cgcggtagcc ttttttgcct ttatccttgacaaatggagt caagaaaccc 1920 atttcagcag ggattaccgt ctggactgct tagcagtagctttgtggaga acatggaggt 1980 gccagcgcct gaatgcaatc tccggctact tgccagtacagccggtagac acgctgagga 2040 tcctgagtct ccagtcaccc caggaacacc aacgccgccagcagccgcag caggagcagc 2100 agcaagagga ggaccgagaa gagaacctga gagccggtctggaccctccg gtggcggagg 2160 aggaggagta gctgacttgt ttcccgagct gcgccgggtgctgactaggt cttccagtgg 2220 acgggagagg gggattaagc gggagaggca tgaggagactagccacagaa ctgaactgac 2280 tgtcagtctg atgagtcgca ggcgcccaga atcggtgtggtggcatgagg tgcagtcgca 2340 ggggatagat gaggtctcag tgatgcatga gaaatattccctagaacaag tcaagacttg 2400 ttggttggag cccgaggatg attgggaggt agccatcaggaattatgcca agctggctct 2460 gaggccagac aagaagtaca agattaccaa actgattaatatcagaaatt cctgctacat 2520 ttcagggaat ggggccgagg tggagatcag tacccaggagagggtggcct tcagatgctg 2580 catgatgaat atgtacccgg gggtggtggg catggagggagtcaccttta tgaacgcgag 2640 gttcaggggt gatgggtata atggggtggt ctttatggccaacaccaagc tgacagtgca 2700 cggatgctcc ttctttggct tcaataacat gtgcattgaggcctggggca gtgtttcagt 2760 gaggggatgc agtttttcag ccaactggat gggggtcgtgggcagaacca agagcatggt 2820 gtcagtgaag aaatgcctgt tcgagaggtg ccacctgggggtgatgagcg agggcgaagc 2880 caaagtcaaa cactgcgcct ctaccgagac gggctgctttgtactgatca agggcaatgc 2940 caaagtcaag cataatatga tctgtggggc ctcggatgagcgcggctacc agatgctgac 3000 ctgcgccggt gggaacagcc atatgctagc caccgtgcatgtggcctcgc acccccgcaa 3060 gacatggccc gagttcgagc acaacgtcat gacccgctgcaatgtgcacc tggggtcccg 3120 ccgaggcatg ttcatgccct accagtgcaa catgcaatttgtgaaggtgc tgctggagcc 3180 cgatgccatg tccagagtga gcctgacggg ggtgtttgacatgaatgtgg agctgtggaa 3240 aattctgaga tatgatgaat ccaagaccag gtgccgggcctgcgaatgcg gaggcaagca 3300 cgccaggctt cagcccgtgt gtgtggaggt gacggaggacctgcgacccg atcatttggt 3360 gttgtcctgc aacgggacgg agttcggctc cagcggggaagaatctgact agagtgagta 3420 gtgtttggga ctgggtggga gcctgcatga tgggcagaatgactaaaatc tgtgtttttc 3480 tgcgcagcag catgagcgga agcgcctcct ttgagggaggggtattcagc ccttatctga 3540 cggggcgtct cccctcctgg gcgggagtgc gtcagaatgtgatgggatcc acggtggacg 3600 gccggcccgt gcagcccgcg aactcttcaa ccctgacctacgcgaccctg agctcctcgt 3660 ccgtggacgc agctgccgcc gcagctgctg cttccgccgccagcgccgtg cgcggaatgg 3720 ccctgggcgc cggctactac agctctctgg tggccaactcgagttccacc aataatcccg 3780 ccagcctgaa cgaggagaag ctgctgctgc tgatggcccagctcgaggcc ctgacccagc 3840 gcctgggcga gctgacccag caggtggctc agctgcaggcggagacgcgg gccgcggttg 3900 ccacggtgaa aaccaaataa aaaatgaatc aataaataaacggagacggt tgttgatttt 3960 aacacagagt cttgaatctt tatttgattt ttcgcgcgcggtaggccctg gaccaccggt 4020 ctcgatcatt gagcacccgg tggatctttt ccaggacccggtagaggtgg gcttggatgt 4080 tgaggtacat gggcatgagc ccgtcccggg ggtggaggtagctccattgc agggcctcgt 4140 gctcgggggt ggtgttgtaa atcacccagt catagcaggggcgcagggcg tggtgctgca 4200 cgatgtcctt gaggaggaga ctgatggcca cgggcagccccttggtgtag gtgttgacga 4260 acctgttgag ctgggaggga tgcatgcggg gggagatgagatgcatcttg gcctggatct 4320 tgagattggc gatgttcccg cccagatccc gccgggggttcatgttgtgc aggaccacca 4380 gcacggtgta tccggtgcac ttggggaatt tgtcatgcaacttggaaggg aaggcgtgaa 4440 agaatttgga gacgcccttg tgaccgccca ggttttccatgcactcatcc atgatgatgg 4500 cgatgggccc gtgggcggcg gcttgggcaa agacgtttcgggggtcggac acatcgtagt 4560 tgtggtcctg ggtgagctcg tcataggcca ttttaatgaatttggggcgg agggtgcccg 4620 actgggggac gaaggtgccc tcgatcccgg gggcgtagttgccctcgcag atctgcatct 4680 cccaggcctt gagctcggag ggggggatca tgtccacctgcggggcgatg aaaaaaacgg 4740 tttccggggc gggggagatg agctgggccg aaagcaggttccggagcagc tgggacttgc 4800 cgcagccggt ggggccgtag atgaccccga tgaccggctgcaggtggtag ttgagggaga 4860 gacagctgcc gtcctcgcgg aggagggggg ccacctcgttcatcatctcg cgcacatgca 4920 tgttctcgcg cacgagttcc gccaggaggc gctcgcccccaagcgagagg agctcttgca 4980 gcgaggcgaa gtttttcagc ggcttgagcc cgtcggccatgggcattttg gagagggtct 5040 gttgcaagag ttccagacgg tcccagagct cggtgatgtgctctagggca tctcgatcca 5100 gcagacctcc tcgtttcgcg ggttggggcg actgcgggagtagggcacca ggcgatgggc 5160 gtccagcgag gccagggtcc ggtccttcca ggggcgcagggtccgcgtca gcgtggtctc 5220 cgtcacggtg aaggggtgcg cgccgggctg ggcgcttgcgagggtgcgct tcaggctcat 5280 ccggctggtc gagaaccgct cccggtcggc gccctgcgcgtcggccaggt agcaattgag 5340 catgagttcg tagttgagcg cctcggccgc gtggcccttggcgcggagct tacctttgga 5400 agtgtgtccg cagacgggac agaggaggga cttgagggcgtagagcttgg gggcgaggaa 5460 gacggactcg ggggcgtagg cgtccgcgcc gcagctggcgcagacggtct cgcactccac 5520 gagccaggtg aggtctggcc ggtcggggtc aaaaacgaggtttcctccgt gctttttgat 5580 gcgtttctta cctctggtct ccatgagctc gtgtccccgctgggtgacaa agaggctgtc 5640 cgtgtccccg tagaccgact ttatgggccg gtcctcgagcggggtgccgc ggtcctcgtc 5700 gtagaggaac cccgcccact ccgagacgaa ggcccgggtccaggccagca cgaaggaggc 5760 cacgtgggag gggtagcggt cgttgtccac cagcgggtccaccttctcca gggtatgcaa 5820 gcacatgtcc ccctcgtcca catccaggaa ggtgattggcttgtaagtgt aggccacgtg 5880 accgggggtc ccggccgggg gggtataaaa gggggcgggcccctgctcgt cctcactgtc 5940 ttccggatcg ctgtccagga gcgccagctg ttggggtaggtattccctct cgaaggcggg 6000 catgacctcg gcactcaggt tgtcagtttc tagaaacgaggaggatttga tattgacggt 6060 gccgttggag acgcctttca tgagcccctc gtccatctggtcagaaaaga cgatcttttt 6120 gttgtcgagc ttggtggcga aggagccgta gagggcgttggagagcagct tggcgatgga 6180 gcgcatggtc tggttctttt ccttgtcggc gcgctccttggcggcgatgt tgagctgcac 6240 gtactcgcgc gccacgcact tccattcggg gaagacggtggtgagcttgt cgggcacgat 6300 tctgacccgc cagccgcggt tgtgcagggt gatgaggtccacgctggtgg ccacctcgcc 6360 gcgcaggggc tcgttggtcc agcagaggcg cccgcccttgcgcgagcaga aggggggcag 6420 cgggtccagc atgagctcgt cgggggggtc ggcgtccacggtgaagatgc cgggcaggag 6480 ctcggggtcg aagtagctga tgcaggtgcc cagatcgtccagcgccgctt gccagtcgcg 6540 cacggccagc gcgcgctcgt aggggctgag gggcgtgccccagggcatgg ggtgcgtgag 6600 cgcggaggcg tacatgccgc agatgtcgta gacgtagaggggctcctcga ggacgccgat 6660 gtaggtgggg tagcagcgcc ccccgcggat gctggcgcgcacgtagtcgt acagctcgtg 6720 cgagggcgcg aggagcccgg tgccgaggtt ggagcgctgcggcttttcgg cgcggtagac 6780 gatctggcgg aagatggcgt gggagttgga ggagatggtgggcctctgga agatgttgaa 6840 gtgggcgtgg ggcagtccga ccgagtccct gatgaagtgggcgtaggagt cctgcagctt 6900 ggcgacgagc tcggcggtga cgaggacgtc cagggcgcagtagtcgaggg tctcttggat 6960 gatgtcgtac ttgagctggc ccttctgctt ccacagctcgcggttgagaa ggaactcttc 7020 gcggtccttc cagtactctt cgagggggaa cccgtcctgatcggcacggt aagagcccac 7080 catgtagaac tggttgacgg ccttgtaggc gcagcagcccttctccacgg ggagggcgta 7140 agcttgcgcg gccttgcgca gggaggtgtg ggtgagggcgaaggtgtcgc gcaccatgac 7200 cttgaggaac tggtgcttga agtcgaggtc gtcgcagccgccctgctccc agagctggaa 7260 gtccgtgcgc ttcttgtagg cggggttggg caaagcgaaagtaacatcgt tgaagaggat 7320 cttgcccgcg cggggcatga agttgcgagt gatgcggaaaggctggggca cctcggcccg 7380 gttgttgatg acctgggcgg cgaggacgat ctcgtcgaagccgttgatgt tgtgcccgac 7440 gatgtagagt tccacgaatc gcgggcggcc cttgacgtggggcagcttct tgagctcgtc 7500 gtaggtgagc tcggcggggt cgctgaggcc gtgctgctcgagggcccagt cggcgaggtg 7560 ggggttggcg ccgaggaagg aagtccagag atccacggccagggcggtct gcaagcggtc 7620 ccggtactga cggaactgct ggcccacggc cattttttcgggggtgacgc agtagaaggt 7680 gcgggggtcg ccgtgccagc ggtcccactt gagctggagggcgaggtcgt gggcgagctc 7740 gacgagcggc gggtccccgg agagtttcat gaccagcatgaaggggacga gctgcttgcc 7800 gaaggacccc atccaggtgt aggtttccac gtcgtaggtgaggaagagcc tttcggtgcg 7860 aggatgcgag ccgatgggga agaactggat ctcctgccaccagttggagg aatggctgtt 7920 gatgtgatgg aagtagaaat gccgacggcg cgccgagcactcgtgcttgt gtttatacaa 7980 gcgtccgcag tgctcgcaac gctgcacggg atgcacgtgctgcacgagct gtacctgggt 8040 tcctttgacg aggaatttca gtgggcagtg gagcgctggcggctgcatct ggtgctgtac 8100 tacgtcctgg ccatcggcgt ggccatcgtc tgcctcgatggtggtcatgc tgacgaggcc 8160 gcgcgggagg caggtccaga cctcggctcg gacgggtcggagagcgagga cgagggcgcg 8220 caggccggag ctgtccaggg tcctgagacg ctgcggagtcaggtcagtgg gcagcggcgg 8280 cgcgcggttg acttgcagga gcttttccag ggcgcgcgggaggtccagat ggtacttgat 8340 ctccacggcg ccgttggtgg cgacgtccac ggcttgcagggtcccgtgcc cctggggcgc 8400 caccaccgtg ccccgtttct tcttgggtgc tggcggcggcggctccatgc ttagaagcgg 8460 cggcgaggac gcgcgccggg cggcaggggc ggctcggggcccggaggcag gggcggcagg 8520 ggcacgtcgg cgccgcgcgc gggcaggttc tggtactgcgcccggagaag actggcgtga 8580 gcgacgacgc gacggttgac gtcctggatc tgacgcctctgggtgaaggc cacgggaccc 8640 gtgagtttga acctgaaaga gagttcgaca gaatcaatctcggtatcgtt gacggcggcc 8700 tgccgcagga tctcttgcac gtcgcccgag ttgtcctggtaggcgatctc ggtcatgaac 8760 tgctcgatct cctcctcctg aaggtctccg cgaccggcgcgctcgacggt ggccgcgagg 8820 tcgttggaga tgcggcccat gagctgcgag aaggcgttcatgccggcctc gttccagacg 8880 cggctgtaga ccacggctcc gtcggggtcg cgcgcgcgcatgaccacctg ggcgaggttg 8940 agctcgacgt ggcgcgtgaa gaccgcgtag ttgcagaggcgctggtagag gtagttgagc 9000 gtggtggcga tgtgctcggt gacgaagaag tacatgatccagcggcggag cggcatctcg 9060 ctgacgtcgc ccagggcttc caagcgctcc atggcctcgtagaagtccac ggcgaagttg 9120 aaaaactggg agttgcgcgc cgagacggtc aactcctcctccagaagacg gatgagctcg 9180 gcgatggtgg cgcgcacctc gcgctcgaag gccccggggggctcctcttc ttccatctcc 9240 tcctcctctt ccatctcctc cactaacatc tcttctacttcctcctcagg aggcggcggc 9300 gggggagggg ccctgcgtcg ccggcggcgc acgggcagacggtcgatgaa gcgctcgatg 9360 gtctccccgc gccggcgacg catggtctcg gtgacggcgcgcccgtcctc gcggggccgc 9420 agcgtgaaga cgccgccgcg catctccagg tggccgccgggggggtctcc gttgggcagg 9480 gagagggcgc tgacgatgca tcttatcaat tggcccgtagggactccgcg caaggacctg 9540 agcgtctcga gatccacggg atccgaaaac cgctgaacgaaggcttcgag ccagtcgcag 9600 tcgcaaggta ggctgagccc ggtttcttgt tcttcgggtatttggtcggg aggcgggcgg 9660 gcgatgctgc tggtgatgaa gttgaagtag gcggtcctgagacggcggat ggtggcgagg 9720 agcaccaggt ccttgggccc ggcttgctgg atgcgcagacggtcggccat gccccaggcg 9780 tggtcctgac acctggcgag gtccttgtag tagtcctgcatgagccgctc cacgggcacc 9840 tcctcctcgc ccgcgcggcc gtgcatgcgc gtgagcccgaacccgcgctg cggctggacg 9900 agcgccaggt cggcgacgac gcgctcggcg aggatggcctgctggatctg ggtgagggtg 9960 gtctggaagt cgtcgaagtc gacgaagcgg tggtaggctccggtgttgat ggtgtaggag 10020 cagttggcca tgacggacca gttgacggtc tggtggccggggcgcacgag ctcgtggtac 10080 ttgaggcgcg agtaggcgcg cgtgtcgaag atgtagtcgttgcaggtgcg cacgaggtac 10140 tggtatccga cgaggaagtg cggcggcggc tggcggtagagcggccatcg ctcggtggcg 10200 ggggcgccgg gcgcgaggtc ctcgagcatg aggcggtggtagccgtagat gtacctggac 10260 atccaggtga tgccggcggc ggtggtggag gcgcgcgggaactcgcggac gcggttccag 10320 atgttgcgca gcggcaggaa gtagttcatg gtggccgcggtctggcccgt gaggcgcgcg 10380 cagtcgtgga tgctctagac atacgggcaa aaacgaaagcggtcagcggc tcgactccgt 10440 ggcctggagg ctaagcgaac gggttgggct gcgcgtgtaccccggttcga gtccctgctc 10500 gaatcaggct ggagccgcag ctaacgtggt actggcactcccgtctcgac ccaagcctgc 10560 taacgaaacc tccaggatac ggaggcgggt cgttttggccattttcgtca ggccggaaat 10620 gaaactagta agcgcggaaa gcggccgtcc gcgatggctcgctgccgtag tctggagaaa 10680 gaatcgccag ggttgcgttg cggtgtgccc cggttcgagcctcagcgctc ggcgccggcc 10740 ggattccgcg gctaacgtgg gcgtggctgc cccgtcgtttccaagacccc ttagccagcc 10800 gacttctcca gttacggagc gagcccctct ttttcttgtgtttttgccag atgcatcccg 10860 tactgcggca gatgcgcccc caccctccac cacaaccgcccctaccgcag cagcagcaac 10920 agccggcgct tctgcccccg ccccagcagc agcagccagccactaccgcg gcggccgccg 10980 tgagcggagc cggcgttcag tatgacctgg ccttggaagagggcgagggg ctggcgcggc 11040 tgggggcgtc gtcgccggag cggcacccgc gcgtgcagatgaaaagggac gctcgcgagg 11100 cctacgtgcc caagcagaac ctgttcagag acaggagcggcgaggagccc gaggagatgc 11160 gcgcctcccg cttccacgcg gggcgggagc tgcggcgcggcctggaccga aagcgggtgc 11220 tgagggacga ggatttcgag gcggacgagc tgacggggatcagccccgcg cgcgcgcacg 11280 tggccgcggc caacctggtc acggcgtacg agcagaccgtgaaggaggag agcaacttcc 11340 aaaaatcctt caacaaccac gtgcgcacgc tgatcgcgcgcgaggaggtg accctgggcc 11400 tgatgcacct gtgggacctg ctggaggcca tcgtgcagaaccccacgagc aagccgctga 11460 cggcgcagct gtttctggtg gtgcagcaca gtcgggacaacgagacgttc agggaggcgc 11520 tgctgaatat caccgagccc gagggccgct ggctcctggacctggtgaac attctgcaga 11580 gcatcgtggt gcaggagcgc gggctgccgc tgtccgagaagctggcggcc atcaacttct 11640 cggtgctgag cctgggcaag tactacgcta ggaagatctacaagaccccg tacgtgccca 11700 tagacaagga ggtgaagatc gacgggtttt acatgcgcatgaccctgaaa gtgctgaccc 11760 tgagcgacga tctgggggtg taccgcaacg acaggatgcaccgcgcggtg agcgccagcc 11820 gccggcgcga gctgagcgac caggagctga tgcacagcctgcagcgggcc ctgaccgggg 11880 ccgggaccga gggggagagc tactttgaca tgggcgcggacctgcgctgg cagcctagcc 11940 gccgggcctt ggaagctgcc ggcggttccc cctacgtggaggaggtggac gatgaggagg 12000 aggagggcga gtacctggaa gactgatggc gcgaccgtatttttgctaga tgcagcaaca 12060 gccaccgccg cctcctgatc ccgcgatgcg ggcggcgctgcagagccagc cgtccggcat 12120 taactcctcg gacgattgga cccaggccat gcaacgcatcatggcgctga cgacccgcaa 12180 tcccgaagcc tttagacagc agcctcaggc caaccgactctcggccatcc tggaggccgt 12240 ggtgccctcg cgctcgaacc ccacgcacga gaaggtgctggccatcgtga acgcgctggt 12300 ggagaacaag gccatccgcg gcgacgaggc cgggctggtgtacaacgcgc tgctggagcg 12360 cgtggcccgc tacaacagca ccaacgtgca gacgaacctggaccgcatgg tgaccgacgt 12420 gcgcgaggcg gtgtcgcagc gcgagcggtt ccaccgcgagtcgaacctgg gctccatggt 12480 ggcgctgaac gccttcctga gcacgcagcc cgccaacgtgccccggggcc aggaggacta 12540 caccaacttc atcagcgcgc tgcggctgat ggtggccgaggtgccccaga gcgaggtgta 12600 ccagtcgggg ccggactact tcttccagac cagtcgccagggcttgcaga ccgtgaacct 12660 gagccaggct ttcaagaact tgcagggact gtggggcgtgcaggccccgg tcggggaccg 12720 cgcgacggtg tcgagcctgc tgacgccgaa ctcgcgcctgctgctgctgc tggtggcgcc 12780 cttcacggac agcggcagcg tgagccgcga ctcgtacctgggctacctgc ttaacctgta 12840 ccgcgaggcc atcgggcagg cgcacgtgga cgagcagacctaccaggaga tcacccacgt 12900 gagccgcgcg ctgggccagg aggacccggg caacctggaggccaccctga acttcctgct 12960 gaccaaccgg tcgcagaaga tcccgcccca gtacgcgctgagcaccgagg aggagcgcat 13020 cctgcgctac gtgcagcaga gcgtggggct gttcctgatgcaggaggggg ccacgcccag 13080 cgccgcgctc gacatgaccg cgcgcaacat ggagcccagcatgtacgccc gcaaccgccc 13140 gttcatcaat aagctgatgg actacttgca tcgggcggccgccatgaact cggactactt 13200 taccaacgcc atcttgaacc cgcactggct cccgccgcccgggttctaca cgggcgagta 13260 cgacatgccc gaccccaacg acgggttcct gtgggacgacgtggacagca gcgtgttctc 13320 gccgcgcccc accaccacca ccgtgtggaa gaaagagggcggggaccggc ggccgtcctc 13380 ggcgctgtcc ggtcgcgcgg gtgctgccgc ggcggtgcccgaggccgcca gccccttccc 13440 gagcctgccc ttttcgctga acagcgtgcg cagcagcgagctgggtcggc tgacgcggcc 13500 gcgcctgctg ggcgaggagg agtacctgaa cgactccttgcttcggcccg agcgcgagaa 13560 gaacttcccc aataacggga tagagagcct ggtggacaagatgagccgct ggaagacgta 13620 cgcgcacgag cacagggacg agccccgagc tagcagcagcaccggcgcca cccgtagacg 13680 ccagcggcac gacaggcagc ggggtctggt gtgggacgatgaggattccg ccgacgacag 13740 cagcgtgttg gacttgggtg ggagtggtgg tggtaacccgttcgctcacc tgcgcccccg 13800 tatcgggcgc ctgatgtaag aatctgaaaa aataaaagacggtactcacc aaggccatgg 13860 cgaccagcgt gcgttcttct ctgttgtttg tagtagt atgatg agg cgc gtg tac 13915 Met Met Arg Arg Val Tyr 1 5 ccg gag ggt cctcct ccc tcg tac gag agc gtg atg cag cag gcg gtg 13963 Pro Glu Gly ProPro Pro Ser Tyr Glu Ser Val Met Gln Gln Ala Val 10 15 20 gcg gcg gcg atgcag ccc ccg ctg gag gcg cct tac gtg ccc ccg cgg 14011 Ala Ala Ala MetGln Pro Pro Leu Glu Ala Pro Tyr Val Pro Pro Arg 25 30 35 tac ctg gcg cctacg gag ggg cgg aac agc att cgt tac tcg gag ctg 14059 Tyr Leu Ala ProThr Glu Gly Arg Asn Ser Ile Arg Tyr Ser Glu Leu 40 45 50 gca ccc ttg tacgat acc acc cgg ttg tac ctg gtg gac aac aag tcg 14107 Ala Pro Leu TyrAsp Thr Thr Arg Leu Tyr Leu Val Asp Asn Lys Ser 55 60 65 70 gcg gac atcgcc tcg ctg aac tac cag aac gac cac agc aac ttc ctg 14155 Ala Asp IleAla Ser Leu Asn Tyr Gln Asn Asp His Ser Asn Phe Leu 75 80 85 acc acc gtggtg cag aac aac gat ttc acc ccc acg gag gcc agc acc 14203 Thr Thr ValVal Gln Asn Asn Asp Phe Thr Pro Thr Glu Ala Ser Thr 90 95 100 cag accatc aac ttt gac gag cgc tcg cgg tgg ggc ggc cag ctg aaa 14251 Gln ThrIle Asn Phe Asp Glu Arg Ser Arg Trp Gly Gly Gln Leu Lys 105 110 115 accatc atg cac acc aac atg ccc aac gtg aac gag ttc atg tac agc 14299 ThrIle Met His Thr Asn Met Pro Asn Val Asn Glu Phe Met Tyr Ser 120 125 130aac aag ttc aag gcg cgg gtg atg gtc tcg cgc aag acc ccc aac ggg 14347Asn Lys Phe Lys Ala Arg Val Met Val Ser Arg Lys Thr Pro Asn Gly 135 140145 150 gtc aca gta aca gat ggt agt cag gac gag ctg acc tac gag tgg gtg14395 Val Thr Val Thr Asp Gly Ser Gln Asp Glu Leu Thr Tyr Glu Trp Val155 160 165 gag ttt gag ctg ccc gag ggc aac ttc tcg gtg acc atg acc atcgat 14443 Glu Phe Glu Leu Pro Glu Gly Asn Phe Ser Val Thr Met Thr IleAsp 170 175 180 ctg atg aac aac gcc atc atc gac aac tac ttg gcg gtg gggcgg cag 14491 Leu Met Asn Asn Ala Ile Ile Asp Asn Tyr Leu Ala Val GlyArg Gln 185 190 195 aac ggg gtg ctg gag agc gac atc ggc gtg aag ttc gacacg cgc aac 14539 Asn Gly Val Leu Glu Ser Asp Ile Gly Val Lys Phe AspThr Arg Asn 200 205 210 ttc cgg ctg ggc tgg gac ccc gtg acc gag ctg gtgatg ccg ggc gtg 14587 Phe Arg Leu Gly Trp Asp Pro Val Thr Glu Leu ValMet Pro Gly Val 215 220 225 230 tac acc aac gag gcc ttc cac ccc gac atcgtc ctg ctg ccc ggc tgc 14635 Tyr Thr Asn Glu Ala Phe His Pro Asp IleVal Leu Leu Pro Gly Cys 235 240 245 ggc gtg gac ttc acc gag agc cgc ctcagc aac ctg ctg ggc atc cgc 14683 Gly Val Asp Phe Thr Glu Ser Arg LeuSer Asn Leu Leu Gly Ile Arg 250 255 260 aag cgg cag ccc ttc cag gag ggcttc cag atc ctg tac gag gac ctg 14731 Lys Arg Gln Pro Phe Gln Glu GlyPhe Gln Ile Leu Tyr Glu Asp Leu 265 270 275 gag ggg ggc aac atc ccc gcgctg ctg gac gtg gac gcc tac gag aaa 14779 Glu Gly Gly Asn Ile Pro AlaLeu Leu Asp Val Asp Ala Tyr Glu Lys 280 285 290 agc aag gag gat agc gccgcc gcg gcg acc gca gcc gtg gcc acc gcc 14827 Ser Lys Glu Asp Ser AlaAla Ala Ala Thr Ala Ala Val Ala Thr Ala 295 300 305 310 tct acc gag gtgcgg ggc gat aat ttt gct agc gcc gcg aca ctg gca 14875 Ser Thr Glu ValArg Gly Asp Asn Phe Ala Ser Ala Ala Thr Leu Ala 315 320 325 gcg gcc gaggcg gct gaa acc gaa agt aag ata gtg atc cag ccg gtg 14923 Ala Ala GluAla Ala Glu Thr Glu Ser Lys Ile Val Ile Gln Pro Val 330 335 340 gag aaggac agc aag gag agg agc tac aac gtg ctc gcg gac aag aaa 14971 Glu LysAsp Ser Lys Glu Arg Ser Tyr Asn Val Leu Ala Asp Lys Lys 345 350 355 aacacc gcc tac cgc agc tgg tac ctg gcc tac aac tac ggc gac ccc 15019 AsnThr Ala Tyr Arg Ser Trp Tyr Leu Ala Tyr Asn Tyr Gly Asp Pro 360 365 370gag aag ggc gtg cgc tcc tgg acg ctg ctc acc acc tcg gac gtc acc 15067Glu Lys Gly Val Arg Ser Trp Thr Leu Leu Thr Thr Ser Asp Val Thr 375 380385 390 tgc ggc gtg gag caa gtc tac tgg tcg ctg ccc gac atg atg caa gac15115 Cys Gly Val Glu Gln Val Tyr Trp Ser Leu Pro Asp Met Met Gln Asp395 400 405 ccg gtc acc ttc cgc tcc acg cgt caa gtt agc aac tac ccg gtggtg 15163 Pro Val Thr Phe Arg Ser Thr Arg Gln Val Ser Asn Tyr Pro ValVal 410 415 420 ggc gcc gag ctc ctg ccc gtc tac tcc aag agc ttc ttc aacgag cag 15211 Gly Ala Glu Leu Leu Pro Val Tyr Ser Lys Ser Phe Phe AsnGlu Gln 425 430 435 gcc gtc tac tcg cag cag ctg cgc gcc ttc acc tcg ctcacg cac gtc 15259 Ala Val Tyr Ser Gln Gln Leu Arg Ala Phe Thr Ser LeuThr His Val 440 445 450 ttc aac cgc ttc ccc gag aac cag atc ctc gtt cgcccg ccc gcg ccc 15307 Phe Asn Arg Phe Pro Glu Asn Gln Ile Leu Val ArgPro Pro Ala Pro 455 460 465 470 acc att acc acc gtc agt gaa aac gtt cctgct ctc aca gat cac ggg 15355 Thr Ile Thr Thr Val Ser Glu Asn Val ProAla Leu Thr Asp His Gly 475 480 485 acc ctg ccg ctg cgc agc agt atc cgggga gtc cag cgc gtg acc gtc 15403 Thr Leu Pro Leu Arg Ser Ser Ile ArgGly Val Gln Arg Val Thr Val 490 495 500 act gac gcc aga cgc cgc acc tgcccc tac gtc tac aag gcc ctg ggc 15451 Thr Asp Ala Arg Arg Arg Thr CysPro Tyr Val Tyr Lys Ala Leu Gly 505 510 515 gta gtc gcg ccg cgc gtc ctctcg agc cgc acc ttc taa aaaatgtcca 15500 Val Val Ala Pro Arg Val Leu SerSer Arg Thr Phe 520 525 530 ttctcatctc gcccagtaat aacaccggtt ggggcctgcgcgcgcccagc aagatgtacg 15560 gaggcgctcg ccaacgctcc acgcaacacc ccgtgcgcgtgcgcgggcac ttccgcgctc 15620 cctggggcgc cctcaagggc cgcgtgcgct cgcgcaccaccgtcgacgac gtgatcgacc 15680 aggtggtggc cgacgcgcgc aactacacgc ccgccgccgcgcccgtctcc accgtggacg 15740 ccgtcatcga cagcgtggtg gccgacgcgc gccggtacgcccgcgccaag agccggcggc 15800 ggcgcatcgc ccggcggcac cggagcaccc ccgccatgcgcgcggcgcga gccttgctgc 15860 gcagggccag gcgcacggga cgcagggcca tgctcagggcggccagacgc gcggcctccg 15920 gcagcagcag cgccggcagg acccgcagac gcgcggccacggcggcggcg gcggccatcg 15980 ccagcatgtc ccgcccgcgg cgcggcaacg tgtactgggtgcgcgacgcc gccaccggtg 16040 tgcgcgtgcc cgtgcgcacc cgcccccctc gcacttgaagatgctgactt cgcgatgttg 16100 atgtgtccca gcggcgagga ggatgtccaa gcgcaaattcaaggaagaga tgctccaggt 16160 catcgcgcct gagatctacg gcccggcggc ggtgaaggaggaaagaaagc cccgcaaact 16220 gaagcgggtc aaaaaggaca aaaaggagga ggaagatgtggacggactgg tggagtttgt 16280 gcgcgagttc gccccccggc ggcgcgtgca gtggcgcgggcggaaagtga aaccggtgct 16340 gcgacccggc accacggtgg tcttcacgcc cggcgagcgttccggctccg cctccaagcg 16400 ctcctacgac gaggtgtacg gggacgagga catcctcgagcaggcggccg aacgtctggg 16460 cgagtttgct tacggcaagc gcagccgccc cgcgcccttgaaagaggagg cggtgtccat 16520 cccgctggac cacggcaacc ccacgccgag cctgaagccggtgaccctgc agcaggtgct 16580 gcctggtgcg gcgccgcgcc ggggcttcaa gcgcgagggcggcgaggatc tgtacccgac 16640 catgcagctg atggtgccca agcgccagaa gctggaggacgtgctggagc acatgaaggt 16700 ggaccccgag gtgcagcccg aggtcaaggt gcggcccatcaagcaggtgg ccccgggcct 16760 gggcgtgcag accgtggaca tcaagatccc cacggagcccatggaaacgc agaccgagcc 16820 cgtgaagccc agcaccagca ccatggaggt gcagacggatccctggatgc cggcaccggc 16880 ttccaccacc cgccgaagac gcaagtacgg cgcggccagcctgctgatgc ccaactacgc 16940 gctgcatcct tccatcatcc ccacgccggg ctaccgcggcacgcgcttct accgcggcta 17000 caccagcagc cgccgccgca agaccaccac ccgccgccgccgtcgtcgca cccgccgcag 17060 cagcaccgcg acttccgccg ccgccctggt gcggagagtgtaccgcagcg ggcgcgagcc 17120 tctgaccctg ccgcgcgcgc gctaccaccc gagcatcgccatttaactac cgcctcctac 17180 ttgcagatat ggccctcaca tgccgcctcc gcgtccccattacgggctac cgaggaagaa 17240 agccgcgccg tagaaggctg acggggaacg ggctgcgtcgccatcaccac cggcggcggc 17300 gcgccatcag caagcggttg gggggaggct tcctgcccgcgctgatgccc atcatcgccg 17360 cggcgatcgg ggcgatcccc ggcatagctt ccgtggcggtgcaggcctct cagcgccact 17420 gagacacagc ttggaaaatt tgtaataaaa aatggactgacgctcctggt cctgtgatgt 17480 gtgtttttag atggaagaca tcaatttttc gtccctggcaccgcgacacg gcacgcggcc 17540 gtttatgggc acctggagcg acatcggcaa cagccaactgaacgggggcg ccttcaattg 17600 gagcagtctc tggagcgggc ttaagaattt cgggtccacgctcaaaacct atggcaacaa 17660 ggcgtggaac agcagcacag ggcaggcgct gagggaaaagctgaaagagc agaacttcca 17720 gcagaaggtg gtcgatggcc tggcctcggg catcaacggggtggtggacc tggccaacca 17780 ggccgtgcag aaacagatca acagccgcct ggacgcggtcccgcccgcgg ggtccgtgga 17840 gatgccccag gtggaggagg agctgcctcc cctggacaagcgcggcgaca agcgaccgcg 17900 tcccgacgcg gaggagacgc tgctgacgca cacggacgagccgcccccgt acgaggaggc 17960 ggtgaaactg ggtctgccca ccacgcggcc cgtggcgcctctggccaccg gggtgctgaa 18020 acccagcagc agcagcagcc agcccgcgac cctggacttgcctccgcctg cttcccgccc 18080 ctccacagtg gctaagcccc tgccgccggt ggccgtcgcgtcgcgcgccc cccgaggccg 18140 cccccaggcg aactggcaga gcactctgaa cagcatcgtgggtctgggag tgcagagtgt 18200 gaagcgccgc cgctgctatt aaaagacact gtagcgcttaacttgcttgt ctgtgtgtat 18260 atgtatgtcc gccgaccaga aggaggagga agaggcgcgtcgccgagttg caag atg 18317 Met gcc acc cca tcg atg ctg ccc cag tgg gcgtac atg cac atc gcc gga 18365 Ala Thr Pro Ser Met Leu Pro Gln Trp AlaTyr Met His Ile Ala Gly 535 540 545 cag gac gct tcg gag tac ctg agt ccgggt ctg gtg cag ttc gcc cgc 18413 Gln Asp Ala Ser Glu Tyr Leu Ser ProGly Leu Val Gln Phe Ala Arg 550 555 560 gcc aca gac acc tac ttc agt ctgggg aac aag ttt agg aac ccc acg 18461 Ala Thr Asp Thr Tyr Phe Ser LeuGly Asn Lys Phe Arg Asn Pro Thr 565 570 575 gtg gcg ccc acg cac gat gtgacc acc gac cgc agc cag cgg ctg acg 18509 Val Ala Pro Thr His Asp ValThr Thr Asp Arg Ser Gln Arg Leu Thr 580 585 590 595 ctg cgc ttc gtg cccgtg gac cgc gag gac aac acc tac tcg tac aaa 18557 Leu Arg Phe Val ProVal Asp Arg Glu Asp Asn Thr Tyr Ser Tyr Lys 600 605 610 gtg cgc tac acgctg gcc gtg ggc gac aac cgc gtg ctg gac atg gcc 18605 Val Arg Tyr ThrLeu Ala Val Gly Asp Asn Arg Val Leu Asp Met Ala 615 620 625 agc acc tacttt gac atc cgc ggc gtg ctg gat cgg ggc cct agc ttc 18653 Ser Thr TyrPhe Asp Ile Arg Gly Val Leu Asp Arg Gly Pro Ser Phe 630 635 640 aaa ccctac tcc ggc acc gct tac aac agc ctg gct ccc aag gga gcg 18701 Lys ProTyr Ser Gly Thr Ala Tyr Asn Ser Leu Ala Pro Lys Gly Ala 645 650 655 cccaac act tgc cag tgg aca tat aaa gct gat ggt gat act ggt aca 18749 ProAsn Thr Cys Gln Trp Thr Tyr Lys Ala Asp Gly Asp Thr Gly Thr 660 665 670675 gaa aaa acc tat aca tat gga aat gcg cct gtg caa ggc att agt att18797 Glu Lys Thr Tyr Thr Tyr Gly Asn Ala Pro Val Gln Gly Ile Ser Ile680 685 690 aca aaa gat ggt att caa ctt gga act gac act gat gat cag cccatt 18845 Thr Lys Asp Gly Ile Gln Leu Gly Thr Asp Thr Asp Asp Gln ProIle 695 700 705 tat gca gat aaa act tat caa cca gag cct caa gtg ggt gatgct gaa 18893 Tyr Ala Asp Lys Thr Tyr Gln Pro Glu Pro Gln Val Gly AspAla Glu 710 715 720 tgg cat gac atc act ggt act gat gaa aaa tat gga ggcaga gct ctc 18941 Trp His Asp Ile Thr Gly Thr Asp Glu Lys Tyr Gly GlyArg Ala Leu 725 730 735 aag cct gac acc aaa atg aag ccc tgc tat ggt tctttt gcc aag cct 18989 Lys Pro Asp Thr Lys Met Lys Pro Cys Tyr Gly SerPhe Ala Lys Pro 740 745 750 755 acc aat aaa gaa gga ggt cag gca aat gtgaaa acc gaa aca ggc ggt 19037 Thr Asn Lys Glu Gly Gly Gln Ala Asn ValLys Thr Glu Thr Gly Gly 760 765 770 acc aaa gaa tat gac att gac atg gcattc ttc gat aat cga agt gca 19085 Thr Lys Glu Tyr Asp Ile Asp Met AlaPhe Phe Asp Asn Arg Ser Ala 775 780 785 gct gcg gct ggc ctg gcc cca gaaatt gtt ttg tat act gag aat gtg 19133 Ala Ala Ala Gly Leu Ala Pro GluIle Val Leu Tyr Thr Glu Asn Val 790 795 800 gat ctg gaa act cca gat actcat att gta tac aag gcg ggc aca gat 19181 Asp Leu Glu Thr Pro Asp ThrHis Ile Val Tyr Lys Ala Gly Thr Asp 805 810 815 gac agc agc tct tct atcaat ttg ggt cag cag tcc atg ccc aac aga 19229 Asp Ser Ser Ser Ser IleAsn Leu Gly Gln Gln Ser Met Pro Asn Arg 820 825 830 835 ccc aac tac attggc ttt aga gac aac ttt atc ggg ctc atg tac tac 19277 Pro Asn Tyr IleGly Phe Arg Asp Asn Phe Ile Gly Leu Met Tyr Tyr 840 845 850 aac agc actggc aac atg ggc gtg ctg gct ggt cag gcc tcc cag ctg 19325 Asn Ser ThrGly Asn Met Gly Val Leu Ala Gly Gln Ala Ser Gln Leu 855 860 865 aat gctgtg gtg gac ttg cag gac aga aac act gaa ctg tcc tac cag 19373 Asn AlaVal Val Asp Leu Gln Asp Arg Asn Thr Glu Leu Ser Tyr Gln 870 875 880 ctcttg ctt gac tct ctg ggc gac aga acc agg tat ttc agt atg tgg 19421 LeuLeu Leu Asp Ser Leu Gly Asp Arg Thr Arg Tyr Phe Ser Met Trp 885 890 895aat cag gcg gtg gac agc tat gac ccc gat gtg cgc att att gaa aat 19469Asn Gln Ala Val Asp Ser Tyr Asp Pro Asp Val Arg Ile Ile Glu Asn 900 905910 915 cac ggt gtg gag gat gaa ctc cct aac tat tgc ttc ccc ctg gat gct19517 His Gly Val Glu Asp Glu Leu Pro Asn Tyr Cys Phe Pro Leu Asp Ala920 925 930 gtg ggt aga act gat act tac cag gga att aag gcc aat ggt gctgat 19565 Val Gly Arg Thr Asp Thr Tyr Gln Gly Ile Lys Ala Asn Gly AlaAsp 935 940 945 caa acc acc tgg acc aaa gat gat act gtt aat gat gct aatgaa ttg 19613 Gln Thr Thr Trp Thr Lys Asp Asp Thr Val Asn Asp Ala AsnGlu Leu 950 955 960 ggc aag ggc aat cct ttc gcc atg gag atc aac atc caggcc aac ctg 19661 Gly Lys Gly Asn Pro Phe Ala Met Glu Ile Asn Ile GlnAla Asn Leu 965 970 975 tgg cgg aac ttc ctc tac gcg aac gtg gcg ctg tacctg ccc gac tcc 19709 Trp Arg Asn Phe Leu Tyr Ala Asn Val Ala Leu TyrLeu Pro Asp Ser 980 985 990 995 tac aag tac acg ccg gcc aac atc acg ctgccg acc aac acc aac 19754 Tyr Lys Tyr Thr Pro Ala Asn Ile Thr Leu ProThr Asn Thr Asn 1000 1005 1010 acc tac gat tac atg aac ggc cgc gtg gtggcg ccc tcg ctg gtg 19799 Thr Tyr Asp Tyr Met Asn Gly Arg Val Val AlaPro Ser Leu Val 1015 1020 1025 gac gcc tac atc aac atc ggg gcg cgc tggtcg ctg gac ccc atg 19844 Asp Ala Tyr Ile Asn Ile Gly Ala Arg Trp SerLeu Asp Pro Met 1030 1035 1040 gac aac gtc aac ccc ttc aac cac cac cgcaac gcg ggc ctg cgc 19889 Asp Asn Val Asn Pro Phe Asn His His Arg AsnAla Gly Leu Arg 1045 1050 1055 tac cgc tcc atg ctc ctg ggc aac ggg cgctac gtg ccc ttc cac 19934 Tyr Arg Ser Met Leu Leu Gly Asn Gly Arg TyrVal Pro Phe His 1060 1065 1070 atc cag gtg ccc caa aag ttc ttc gcc atcaag agc ctc ctg ctc 19979 Ile Gln Val Pro Gln Lys Phe Phe Ala Ile LysSer Leu Leu Leu 1075 1080 1085 ctg ccc ggg tcc tac acc tac gag tgg aacttc cgc aag gac gtc 20024 Leu Pro Gly Ser Tyr Thr Tyr Glu Trp Asn PheArg Lys Asp Val 1090 1095 1100 aac atg atc ctg cag agc tcc ctc ggc aacgac ctg cgc acg gac 20069 Asn Met Ile Leu Gln Ser Ser Leu Gly Asn AspLeu Arg Thr Asp 1105 1110 1115 ggg gcc tcc atc gcc ttc acc agc atc aacctc tac gcc acc ttc 20114 Gly Ala Ser Ile Ala Phe Thr Ser Ile Asn LeuTyr Ala Thr Phe 1120 1125 1130 ttc ccc atg gcg cac aac acc gcc tcc acgctc gag gcc atg ctg 20159 Phe Pro Met Ala His Asn Thr Ala Ser Thr LeuGlu Ala Met Leu 1135 1140 1145 cgc aac gac acc aac gac cag tcc ttc aacgac tac ctc tcg gcg 20204 Arg Asn Asp Thr Asn Asp Gln Ser Phe Asn AspTyr Leu Ser Ala 1150 1155 1160 gcc aac atg ctc tac ccc atc ccg gcc aacgcc acc aac gtg ccc 20249 Ala Asn Met Leu Tyr Pro Ile Pro Ala Asn AlaThr Asn Val Pro 1165 1170 1175 atc tcc atc ccc tcg cgc aac tgg gcc gccttc cgc gga tgg tcc 20294 Ile Ser Ile Pro Ser Arg Asn Trp Ala Ala PheArg Gly Trp Ser 1180 1185 1190 ttc acg cgc ctc aag acc cgc gag acg ccctcg ctc ggc tcc ggg 20339 Phe Thr Arg Leu Lys Thr Arg Glu Thr Pro SerLeu Gly Ser Gly 1195 1200 1205 ttc gac ccc tac ttc gtc tac tcg ggc tccatc ccc tac ctc gac 20384 Phe Asp Pro Tyr Phe Val Tyr Ser Gly Ser IlePro Tyr Leu Asp 1210 1215 1220 ggc acc ttc tac ctc aac cac acc ttc aagaag gtc tcc atc acc 20429 Gly Thr Phe Tyr Leu Asn His Thr Phe Lys LysVal Ser Ile Thr 1225 1230 1235 ttc gac tcc tcc gtc agc tgg ccc ggc aacgac cgc ctc ctg acg 20474 Phe Asp Ser Ser Val Ser Trp Pro Gly Asn AspArg Leu Leu Thr 1240 1245 1250 ccc aac gag ttc gaa atc aag cgc acc gtcgac gga gag ggg tac 20519 Pro Asn Glu Phe Glu Ile Lys Arg Thr Val AspGly Glu Gly Tyr 1255 1260 1265 aac gtg gcc cag tgc aac atg acc aag gactgg ttc ctg gtc cag 20564 Asn Val Ala Gln Cys Asn Met Thr Lys Asp TrpPhe Leu Val Gln 1270 1275 1280 atg ctg gcc cac tac aac atc ggc tac cagggc ttc tac gtg ccc 20609 Met Leu Ala His Tyr Asn Ile Gly Tyr Gln GlyPhe Tyr Val Pro 1285 1290 1295 gag ggc tac aag gac cgc atg tac tcc ttcttc cgc aac ttc cag 20654 Glu Gly Tyr Lys Asp Arg Met Tyr Ser Phe PheArg Asn Phe Gln 1300 1305 1310 ccc atg agc cgc cag gtc gtg gac gag gtcaac tac aag gac tac 20699 Pro Met Ser Arg Gln Val Val Asp Glu Val AsnTyr Lys Asp Tyr 1315 1320 1325 cag gcc gtc acc ctg gcc tac cag cac aacaac tcg ggc ttc gtc 20744 Gln Ala Val Thr Leu Ala Tyr Gln His Asn AsnSer Gly Phe Val 1330 1335 1340 ggc tac ctc gcg ccc acc atg cgc cag ggacag ccc tac ccc gcc 20789 Gly Tyr Leu Ala Pro Thr Met Arg Gln Gly GlnPro Tyr Pro Ala 1345 1350 1355 aac tac ccc tac ccg ctc atc ggc aag agcgcc gtc gcc agc gtc 20834 Asn Tyr Pro Tyr Pro Leu Ile Gly Lys Ser AlaVal Ala Ser Val 1360 1365 1370 acc cag aaa aag ttc ctc tgc gac cgg gtcatg tgg cgc atc ccc 20879 Thr Gln Lys Lys Phe Leu Cys Asp Arg Val MetTrp Arg Ile Pro 1375 1380 1385 ttc tcc agc aac ttc atg tcc atg ggc gcgctc acc gac ctc ggc 20924 Phe Ser Ser Asn Phe Met Ser Met Gly Ala LeuThr Asp Leu Gly 1390 1395 1400 cag aac atg ctc tac gcc aac tcc gcc cacgcg cta gac atg aat 20969 Gln Asn Met Leu Tyr Ala Asn Ser Ala His AlaLeu Asp Met Asn 1405 1410 1415 ttc gaa gtc gac ccc atg gat gag tcc accctt ctc tat gtt gtc 21014 Phe Glu Val Asp Pro Met Asp Glu Ser Thr LeuLeu Tyr Val Val 1420 1425 1430 ttc gaa gtc ttc gac gtc gtc cga gtg caccag ccc cac cgc ggc 21059 Phe Glu Val Phe Asp Val Val Arg Val His GlnPro His Arg Gly 1435 1440 1445 gtc atc gag gcc gtc tac ctg cgc acg cccttc tcg gcc ggc aac 21104 Val Ile Glu Ala Val Tyr Leu Arg Thr Pro PheSer Ala Gly Asn 1450 1455 1460 gcc acc acc taa gccccgctct tgcttcttgcaagatgacgg cctgtgcggg 21156 Ala Thr Thr ctccggcgag caggagctca gggccatcctccgcgacctg ggctgcgggc cctgcttcct 21216 gggcaccttc gacaagcgct tcccgggattcatggccccg cacaagctgg cctgcgccat 21276 cgtcaacacg gccggccgcg agaccgggggcgagcactgg ctggccttcg cctggaaccc 21336 gcgctcccac acctgctacc tcttcgaccccttcgggttc tcggacgagc gcctcaagca 21396 gatctaccag ttcgagtacg agggcctgctgcgccgcagc gccctggcca ccgaggaccg 21456 ctgcgtcacc ctggaaaagt ccacccagaccgtgcagggt ccgcgctcgg ccgcctgcgg 21516 gctcttctgc tgcatgttcc tgcacgccttcgtgcactgg cccgaccgcc ccatggacaa 21576 gaaccccacc atgaacttgc tgacgggggtgcccaacggc atgctccagt cgccccaggt 21636 ggaacccacc ctgcgccgca accaggaggcgctctaccgc ttcctcaacg cccactccgc 21696 ctactttcgc tcccaccgcg cgcgcatcgagaaggccacc gccttcgacc gcatgaatca 21756 agacatgtaa accgtgtgtg tatgtgaatgctttattcat aataaacagc acatgtttat 21816 gccacctttt ctgaggctct gactttatttagaaatcgaa ggggttctgc cggctctcgg 21876 cgtgccccgc gggcagggat acgttgcggaactggtactt gggcagccac ttgaactcgg 21936 ggatcagcag cttcggcacg gggaggtcggggaacgagtc gctccacagc ttgcgcgtga 21996 gttgcagggc gcccagcagg tcgggcgcggagatcttgaa atcgcagttg ggacccgcgt 22056 tctgcgcgcg ggagttgcgg tacacggggttgcagcactg gaacaccatc agggccgggt 22116 gcttcacgct cgccagcacc gtcgcgtcggtgatgccctc cacgtccaga tcctcggcgt 22176 tggccatccc gaagggggtc atcttgcaggtctgccgccc catgctgggc acgcagccgg 22236 gcttgtggtt gcaatcgcag tgcagggggatcagcatcat ctgggcctgc tcggagctca 22296 tgcccgggta catggccttc atgaaagcctccagctggcg gaaggcctgc tgcgccttgc 22356 cgccctcggt gaagaagacc ccgcaggacttgctagagaa ctggttggtg gcgcagccgg 22416 cgtcgtgcac gcagcagcgc gcgtcgttgttggccagctg caccacgctg cgcccccagc 22476 ggttctgggt gatcttggcc cggtcggggttctccttcag cgcgcgctgc ccgttctcgc 22536 tcgccacatc catctcgatc gtgtgctccttctggatcat cacggtcccg tgcaggcatc 22596 gcagcttgcc ctcggcctcg gtgcacccgtgcagccacag cgcgcagccg gtgcactccc 22656 agttcttgtg ggcgatctgg gagtgcgagtgcacgaagcc ctgcaggaag cggcccatca 22716 tcgtggtcag ggtcttgttg ctggtgaaggtcagcgggat gccgcggtgc tcctcgttca 22776 catacaggtg gcagatgcgg cggtacacctcgccctgctc gggcatcagc tggaaggcgg 22836 acttcaggtc gctctccacg cggtaccggtccatcagcag cgtcatgact tccatgccct 22896 tctcccaggc cgagacgatc ggcaggctcagggggttctt caccgccgtt gtcatcttag 22956 tcgccgccgc tgaggtcagg gggtcgttctcgtccagggt ctcaaacact cgcttgccgt 23016 ccttctcggt gatgcgcacg gggggaaagctgaagcccac ggccgccagc tcctcctcgg 23076 cctgcctttc gtcctcgctg tcctggctgatgtcttgcaa aggcacatgc ttggtcttgc 23136 ggggtttctt tttgggcggc agaggcggcggcggagacgt gctgggcgag cgcgagttct 23196 cgctcaccac gactatttct tcttcttggccgtcgtccga gaccacgcgg cggtaggcat 23256 gcctcttctg gggcagaggc ggaggcgacgggctctcgcg gttcggcggg cggctggcag 23316 agccccttcc gcgttcgggg gtgcgctcctggcggcgctg ctctgactga cttcctccgc 23376 ggccggccat tgtgttctcc tagggagcaacaagcatgga gactcagcca tcgtcgccaa 23436 catcgccatc tgcccccgcc gccgccgacgagaaccagca gcagaatgaa agcttaaccg 23496 ccccgccgcc cagccccacc tccgacgccgccgcggcccc agacatgcaa gagatggagg 23556 aatccatcga gattgacctg ggctacgtgacgcccgcgga gcacgaggag gagctggcag 23616 cgcgcttttc agccccggaa gagaaccaccaagagcagcc agagcaggaa gcagagagcg 23676 agcagcagca ggctgggctc gagcatggcgactacctgag cggggcagag gacgtgctca 23736 tcaagcatct ggcccgccaa tgcatcatcgtcaaggacgc gctgctcgac cgcgccgagg 23796 tgcccctcag cgtggcggag ctcagccgcgcctacgagcg caacctcttc tcgccgcgcg 23856 tgccccccaa gcgccagccc aacggcacctgcgagcccaa cccgcgcctc aacttctacc 23916 cggtcttcgc ggtgcccgag gccctggccacctaccacct ctttttcaag aaccaaagga 23976 tccccgtctc ctgccgcgcc aaccgcacccgcgccgacgc cctgctcaac ctgggtcccg 24036 gcgcccgcct acctgatatc gcctccttggaagaggttcc caagatcttc gagggtctgg 24096 gcagcgacga gactcgggcc gcgaacgctctgcaaggaag cggagaggag catgagcacc 24156 acagcgccct ggtggagttg gaaggcgacaacgcgcgcct ggcggtgctc aagcgcacgg 24216 tcgagctgac ccacttcgcc tacccggcgctcaacctgcc ccccaaggtc atgagcgccg 24276 tcatggacca ggtgctcatc aagcgcgcctcgcccctctc ggatgaggac atgcaggacc 24336 ccgagagctc ggacgagggc aagcccgtggtcagcgacga gcagctggcg cgctggctgg 24396 gagcgagtag caccccccag agcttggaagagcggcgcaa gctcatgatg gccgtggtcc 24456 tggtgaccgt ggagctggag tgtctgcgccgcttcttcgc cgacgcagag accctgcgca 24516 aggtcgagga gaacctgcac tacctcttcaggcacgggtt tgtgcgccag gcctgcaaga 24576 tctccaacgt ggagctgacc aacctggtctcctacatggg catcctgcac gagaaccgcc 24636 tggggcagaa cgtgctgcac accaccctgcgcggggaggc ccgccgcgac tacatccgcg 24696 actgcgtcta cctgtacctc tgccacacctggcagacggg catgggcgtg tggcagcagt 24756 gcctggagga gcagaacctg aaagagctctgcaagctcct gcagaagaac ctgaaggccc 24816 tgtggaccgg gttcgacgag cgcaccaccgcctcggacct ggccgacctc atcttccccg 24876 agcgcctgcg gctgacgctg cgcaacggactgcccgactt tatgagtcaa agcatgttgc 24936 aaaactttcg ctctttcatc ctcgaacgctccgggatcct gcccgccacc tgctccgcgc 24996 tgccctcgga cttcgtgccg ctgaccttccgcgagtgccc cccgccgctc tggagccact 25056 gctacctgct gcgcctggcc aactacctggcctaccactc ggacgtgatc gaggacgtca 25116 gcggcgaggg tctgctcgag tgccactgccgctgcaacct ctgcacgccg caccgctccc 25176 tggcctgcaa cccccagctg ctgagcgagacccagatcat cggcaccttc gagttgcaag 25236 gccccggcga gggcaagggg ggtctgaaactcaccccggg gctgtggacc tcggcctact 25296 tgcgcaagtt cgtgcccgag gactaccatcccttcgagat caggttctac gaggaccaat 25356 cccagccgcc caaggccgaa ctgtcggcctgcgtcatcac ccagggggcc atcctggccc 25416 aattgcaagc catccagaaa tcccgccaagaatttctgct gaaaaagggc cacggggtct 25476 acctggaccc ccagaccgga gaggagctcaaccccagctt cccccaggat gccccgagga 25536 agcagcaaga agctgaaagt ggagctgccgccgccggagg atttggagga agactgggag 25596 agcagtcagg cagaggagga ggagatggaagactgggaca gcactcaggc agaggaggac 25656 agcctgcaag acagtctgga agacgaggtggaggaggagg cagaggaaga agcagccgcc 25716 gccagaccgt cgtcctcggc ggagaaagcaagcagcacgg ataccatctc cgctccgggt 25776 cggggtcgcg gcgaccgggc ccacagtaggtgggacgaga ccgggcgctt cccgaacccc 25836 accacccaga ccggtaagaa ggagcggcagggatacaagt cctggcgggg gcacaaaaac 25896 gccatcgtct cctgcttgca agcctgcgggggcaacatct ccttcacccg ccgctacctg 25956 ctcttccacc gcggggtgaa cttcccccgcaacatcttgc attactaccg tcacctccac 26016 agcccctact actgtttcca agaagaggcagaaacccagc agcagcagaa aaccagcggc 26076 agcagcagct agaaaatcca cagcggcggcaggtggactg aggatcgcag cgaacgagcc 26136 ggcgcagacc cgggagctga ggaaccggatctttcccacc ctctatgcca tcttccagca 26196 gagtcggggg caggagcagg aactgaaagtcaagaaccgt tctctgcgct cgctcacccg 26256 cagttgtctg tatcacaaga gcgaagaccaacttcagcgc actctcgagg acgccgaggc 26316 tctcttcaac aagtactgcg cgctcactcttaaagagtag cccgcgcccg cccacacacg 26376 gaaaaaggcg ggaattacgt caccacctgcgcccttcgcc cgaccatcat catgagcaaa 26436 gagattccca cgccttacat gtggagctaccagccccaga tgggcctggc cgccggcgcc 26496 gcccaggact actccacccg catgaactggctcagcgccg ggcccgcgat gatctcacgg 26556 gtgaatgaca tccgcgcccg ccgaaaccagatactcctag aacagtcagc gatcaccgcc 26616 acgccccgcc atcaccttaa tccgcgtaattggcccgccg ccctggtgta ccaggaaatt 26676 ccccagccca cgaccgtact acttccgcgagacgcccagg ccgaagtcca gctgactaac 26736 tcaggtgtcc agctggccgg cggcgccgccctgtgtcgtc accgccccgc tcagggtata 26796 aagcggctgg tgatccgagg cagaggcacacagctcaacg acgaggtggt gagctcttcg 26856 ctgggtctgc gacctgacgg agtcttccaactcgccggat cggggagatc ttccttcacg 26916 cctcgtcagg ccgtcctgac tttggagagttcgtcctcgc agccccgctc gggtggcatc 26976 ggcactctcc agttcgtgga ggagttcactccctcggtct acttcaaccc cttctccggc 27036 tcccccggcc actacccgga cgagttcatcccgaacttcg acgccatcag cgagtcggtg 27096 gacggctacg attgaatgtc ccatggtggcgcagctgacc tagctcggct tcgacacctg 27156 gaccactgcc gccgcttccg ctgcttcgctcgggatctcg ccgagtttgc ctactttgag 27216 ctgcccgagg agcaccctca gggcccggcccacggagtgc ggatcatcgt cgaagggggc 27276 ctcgactccc acctgcttcg gatcttcagccagcgaccga tcctggtcga gcgcgagcaa 27336 ggacagaccc ttctgaccct gtactgcatctgcaaccacc ccggcctgca tgaaagtctt 27396 tgttgtctgc tgtgtactga gtataataaaagctgagatc agcgactact ccggactcga 27456 ttgtggtgtt cctgctatca accggtccctgttcttcacc gggaacgaga ccgagctcca 27516 gcttcagtgt aagccccaca agaagtacctcacctggctg ttccagggct ccccgatcgc 27576 cgttgtcaac cactgcgaca acgacggagtcctgctgagc ggccccgcca accttacttt 27636 ttccacccgc agaagcaagc tccagctcttccaacccttc ctccccggga cctatcagtg 27696 cgtctcggga ccctgccatc acaccttccacctgatcccg aataccacag cgccgctccc 27756 cgctactaac aaccaaacta cccaccatcgccaccgtcgc gacctttctg aatctaacac 27816 taccacccac accggaggtg agctccgaggtcgaccaacc tctgggattt actacggccc 27876 ctgggaggtg gtggggttaa tagcgctaggcctagttgtg ggtgggcttt tggctctctg 27936 ctacctatac ctcccttgct gttcgtacttagtggtgctg tgttgctggt ttaagaaatg 27996 gggaagatca ccctagtgag ctgcggtgcgctggtggcgg tggtggtgtt ttcgattgtg 28056 ggactgggcg gcgcggctgt agtgaaggagaaggccgatc cctgcttgca tttcaatccc 28116 gacaattgcc agctgagttt tcagcccgatggcaatcggt gcgcggtgct gatcaagtgc 28176 ggatgggaat gcgagaacgt gagaatcgagtacaataaca agactcggaa caatactctc 28236 gcgtccgtgt ggcagcccgg ggaccccgagtggtacaccg tctctgtccc cggtgctgac 28296 ggctccccgc gcaccgtgaa caatactttcatttttgcgc acatgtgcga cacggtcatg 28356 tggatgagca agcagtacga tatgtggccccccacgaagg agaacatcgt ggtcttctcc 28416 atcgcttaca gcgcgtgcac ggcgctaatcaccgctatcg tgtgcctgag cattcacatg 28476 ctcatcgcta ttcgccccag aaataatgccgaaaaagaga aacagccata acacgttttt 28536 tcacacacct ttttcagacc atggcctctgttaaattttt gcttttattt gccagtctca 28596 ttactgttat aagtaatgag aaactcactatttacattgg cactaaccac actttagacg 28656 gaattccaaa atcctcatgg tattgctattttgatcaaga tccagactta actatagaac 28716 tgtgtggtaa caagggaaaa aatacaagcattcatttaat taactttaat tgcggagaca 28776 atttgaaatt aattaatatc actaaagagtatggaggtat gtattactat gttgcagaaa 28836 ataacaacat gcagttttat gaagttactgtaactaatcc caccacacct agaacaacaa 28896 caaccaccac cacaaaaact acacctgttaccactatgca gctcactacc aataacattt 28956 ttgccatgcg tcaaatggtc aacaatagcactcaacccac cccacccagt gaggaaattc 29016 ccaaatccat gattggcatt attgttgctgtagtggtgtg catgttgatc atcgccttgt 29076 gcatggtgta ctatgccttc tgctacagaaagcacagact gaacgacaag ctggaacact 29136 tactaagtgt tgaattttaa ttttttagaaccatgaagat cctaggcctt ttaatttttt 29196 ctatcattac ctctgctcta tgcaattctgacaatgagga cgttactgtc gttgtcggaa 29256 ccaattatac actgaaaggt ccagcgaagggtatgctttc gtggtattgc tggtttggaa 29316 ctgacgagca acagacagag ctctgcaatgctcaaaaagg caaaacctca aattctaaaa 29376 tctctaatta tcaatgcaat ggcactgacttagtactgct caatgtcacg aaagcatatg 29436 ctggcagcta cacctgccct ggagatgatactgagaacat gattttttac aaagtggaag 29496 tggttgatcc cactactcca cctccacccaccacaactac tcacaccaca cacacagaac 29556 aaaccacagc agaggaggca gcaaagttagccttgcaggt ccaagacagt tcatttgttg 29616 gcattacccc tacacctgat cagcggtgtccggggctgct cgtcagcggc attgtcggtg 29676 tgctttcggg attagcagtc ataatcatctgcatgttcat ttttgcttgc tgctatagaa 29736 ggctttaccg acaaaaatca gacccactgctgaacctcta tgtttaattt tttccagagc 29796 catgaaggca gttagcactc tagttttttgttctttgatt ggcactgttt ttagtgttag 29856 ctttttgaaa caaatcaatg ttactgagggggaaaatgtg acactggtag gcgtagaggg 29916 tgctcaaaat accacctgga caaaattccatctagatggg tggaaagaaa tttgcacctg 29976 gaatgtcagt acttatacat gtgaaggagttaatcttacc attgtcaatg tcagccaaat 30036 tcaaaagggt tggattaaag ggcaatctgttagtgttagc aatagtgggt actataccca 30096 gcatactctt atctatgaca ttatagttataccactgcct acacctagcc cacctagcac 30156 taccacacag acaacccaca ctacacaaacaaccacatac agtacatcaa atcagcctac 30216 caccactaca acagcagagg ttgccagctcgtctggggtc cgagtggcat ttttgatgtt 30276 ggccccatct agcagtccca ctgctagtaccaatgagcag actactgaat ttttgtccac 30336 tgtcgagagc cacaccacag ctacctcgagtgccttctct agcaccgcca atctatcctc 30396 gctttcctct acaccaatca gtcccgctactactcctacc cccgctattc tccccactcc 30456 cctgaagcaa acagacggcg acatgcaatggcagatcacc ctgctcattg tgatcgggtt 30516 ggtcatcctg gccgtgttgc tctactacatcttctgccgc cgcattccca acgcgcaccg 30576 caagccggcc tacaagccca tcgttgtcgggcagccggag ccgcttcagg tggaaggggg 30636 tctaaggaat cttctcttct cttttacagtatggtgattg aattatgatt cctagacaaa 30696 tcttgatcac tattcttatc tgcctcctccaagtctgtgc caccctcgct ctggtggcca 30756 acgccagtcc agactgtatt gggcccttcgcctcctacgt gctctttgcc ttcatcacct 30816 gcatctgctg ctgtagcata gtctgcctgcttatcacctt cttccagttc attgactgga 30876 tctttgtgcg catcgcctac ctgcgccaccacccccagta ccgcgaccag cgagtggcgc 30936 ggctgctcag gatcctctga taagcatgcgggctctgcta cttctcgcgc ttctgctgtt 30996 agtgctcccc cgtcccgtcg acccccggacccccacccag tcccccgagg aggtccgcaa 31056 atgcaaattc caagaaccct ggaaattcctcaaatgctac cgccaaaaat cagacatgca 31116 tcccagctgg atcatgatca ttgggatcgtgaacattctg gcctgcaccc tcatctcctt 31176 tgtgatttac ccctgctttg actttggttggaactcgcca gaggcgctct atctcccgcc 31236 tgaacctgac acaccaccac agcaacctcaggcacacgca ctaccaccac caccacagcc 31296 taggccacaa tacatgccca tattagactatgaggccgag ccacagcgac ccatgctccc 31356 cgctattagt tacttcaatc taaccggcggagatgactga cccactggcc aacaacaacg 31416 tcaacgacct tctcctggac atggacggccgcgcctcgga gcagcgactc gcccaacttc 31476 gcattcgcca gcagcaggag agagccgtcaaggagctgca ggacggcata gccatccacc 31536 agtgcaagaa aggcatcttc tgcctggtgaaacaggccaa gatctcctac gaggtcaccc 31596 agaccgacca tcgcctctcc tacgagctcctgcagcagcg ccagaagttc acctgcctgg 31656 tcggagtcaa ccccatcgtc atcacccagcagtcgggcga taccaagggg tgcatccact 31716 gctcctgcga ctcccccgac tgcgtccacactctgatcaa gaccctctgc ggcctccgcg 31776 acctcctccc catgaactaa tcacccccttatccagtgaa ataaagatca tattgatgat 31836 ttgagtttaa taaaaataaa gaatcacttacttgaaatct gataccaggt ctctgtccat 31896 gttttctgcc aacaccactt cactcccctcttcccagctc tggtactgca ggccccggcg 31956 ggctgcaaac ttcctccaca ccctgaaggggatgtcaaat tcctcctgtc cctcaatctt 32016 cattttatct tctatcag atg tcc aaaaag cgc gtc cgg gtg gat gat gac 32067 Met Ser Lys Lys Arg Val Arg ValAsp Asp Asp 1465 1470 ttc gac ccc gtc tac ccc tac gat gca gac aac gcaccg acc gtg 32112 Phe Asp Pro Val Tyr Pro Tyr Asp Ala Asp Asn Ala ProThr Val 1475 1480 1485 ccc ttc atc aac ccc ccc ttc gtc tct tca gat ggattc caa gag 32157 Pro Phe Ile Asn Pro Pro Phe Val Ser Ser Asp Gly PheGln Glu 1490 1495 1500 aag ccc ctg ggg gtg ctg tcc ctg cgt ctg gcc gatccc gtc acc 32202 Lys Pro Leu Gly Val Leu Ser Leu Arg Leu Ala Asp ProVal Thr 1505 1510 1515 acc aag aac ggg gaa atc acc ctc aag ctg gga gatggg gtg gac 32247 Thr Lys Asn Gly Glu Ile Thr Leu Lys Leu Gly Asp GlyVal Asp 1520 1525 1530 ctc gac tcc tcg gga aaa ctc atc tcc aac acg gccacc aag gcc 32292 Leu Asp Ser Ser Gly Lys Leu Ile Ser Asn Thr Ala ThrLys Ala 1535 1540 1545 gcc gcc cct ctc agt ttt tcc aac aac acc att tccctt aac atg 32337 Ala Ala Pro Leu Ser Phe Ser Asn Asn Thr Ile Ser LeuAsn Met 1550 1555 1560 gat acc cct ttt tac aac aac aat gga aag tta ggcatg aaa gtc 32382 Asp Thr Pro Phe Tyr Asn Asn Asn Gly Lys Leu Gly MetLys Val 1565 1570 1575 act gct cca ctg aag ata cta gac aca gac ttg ctaaaa aca ctt 32427 Thr Ala Pro Leu Lys Ile Leu Asp Thr Asp Leu Leu LysThr Leu 1580 1585 1590 gtt gta gct tat gga caa ggt tta gga aca aac accact ggt gcc 32472 Val Val Ala Tyr Gly Gln Gly Leu Gly Thr Asn Thr ThrGly Ala 1595 1600 1605 ctt gtt gcc caa cta gca tcc cca ctt gct ttt gatagc aat agc 32517 Leu Val Ala Gln Leu Ala Ser Pro Leu Ala Phe Asp SerAsn Ser 1610 1615 1620 aaa att gcc ctt aat tta ggc aat gga cca ttg aaagtg gat gca 32562 Lys Ile Ala Leu Asn Leu Gly Asn Gly Pro Leu Lys ValAsp Ala 1625 1630 1635 aat aga ctg aac atc aat tgc aat aga gga ctc tatgtt act acc 32607 Asn Arg Leu Asn Ile Asn Cys Asn Arg Gly Leu Tyr ValThr Thr 1640 1645 1650 aca aaa gat gca ctg gaa gcc aat ata agt tgg gctaat gct atg 32652 Thr Lys Asp Ala Leu Glu Ala Asn Ile Ser Trp Ala AsnAla Met 1655 1660 1665 aca ttt ata gga aat gcc atg ggt gtc aat att gataca caa aaa 32697 Thr Phe Ile Gly Asn Ala Met Gly Val Asn Ile Asp ThrGln Lys 1670 1675 1680 ggc ttg caa ttt ggc acc act agt acc gtc gca gatgtt aaa aac 32742 Gly Leu Gln Phe Gly Thr Thr Ser Thr Val Ala Asp ValLys Asn 1685 1690 1695 gct tac ccc ata caa atc aaa ctt gga gct ggt ctcaca ttt gac 32787 Ala Tyr Pro Ile Gln Ile Lys Leu Gly Ala Gly Leu ThrPhe Asp 1700 1705 1710 agc aca ggt gca att gtt gca tgg aac aaa gat gatgac aag ctt 32832 Ser Thr Gly Ala Ile Val Ala Trp Asn Lys Asp Asp AspLys Leu 1715 1720 1725 aca cta tgg acc aca gcc gac ccc tct cca aat tgtcac ata tat 32877 Thr Leu Trp Thr Thr Ala Asp Pro Ser Pro Asn Cys HisIle Tyr 1730 1735 1740 tct gaa aag gat gct aag ctt aca ctt tgc ttg acaaag tgt ggc 32922 Ser Glu Lys Asp Ala Lys Leu Thr Leu Cys Leu Thr LysCys Gly 1745 1750 1755 agt cag att ctg ggc act gtt tcc ctc ata gct gttgat act ggc 32967 Ser Gln Ile Leu Gly Thr Val Ser Leu Ile Ala Val AspThr Gly 1760 1765 1770 agt tta aat ccc ata aca gga aca gta acc act gctctt gtc tca 33012 Ser Leu Asn Pro Ile Thr Gly Thr Val Thr Thr Ala LeuVal Ser 1775 1780 1785 ctt aaa ttc gat gca aat gga gtt ttg caa agc agctca aca cta 33057 Leu Lys Phe Asp Ala Asn Gly Val Leu Gln Ser Ser SerThr Leu 1790 1795 1800 gac tca gac tat tgg aat ttc aga cag gga gat gttaca cct gct 33102 Asp Ser Asp Tyr Trp Asn Phe Arg Gln Gly Asp Val ThrPro Ala 1805 1810 1815 gaa gcc tat act aat gct ata ggt ttc atg ccc aatcta aaa gca 33147 Glu Ala Tyr Thr Asn Ala Ile Gly Phe Met Pro Asn LeuLys Ala 1820 1825 1830 tac cct aaa aac aca agt gga gct gca aaa agt cacatt gtt ggg 33192 Tyr Pro Lys Asn Thr Ser Gly Ala Ala Lys Ser His IleVal Gly 1835 1840 1845 aaa gtg tac cta cat ggg gat aca ggc aaa cca ctggac ctc att 33237 Lys Val Tyr Leu His Gly Asp Thr Gly Lys Pro Leu AspLeu Ile 1850 1855 1860 att act ttc aat gaa aca agt gat gaa tct tgc acttac tgt att 33282 Ile Thr Phe Asn Glu Thr Ser Asp Glu Ser Cys Thr TyrCys Ile 1865 1870 1875 aac ttt caa tgg cag tgg ggg gct gat caa tat aaaaat gaa aca 33327 Asn Phe Gln Trp Gln Trp Gly Ala Asp Gln Tyr Lys AsnGlu Thr 1880 1885 1890 ctt gcc gtc agt tca ttc acc ttt tcc tat att gctaaa gaa taa 33372 Leu Ala Val Ser Ser Phe Thr Phe Ser Tyr Ile Ala LysGlu 1895 1900 1905 accccactct gtaccccatc tctgtctatg gaaaaaactctgaaacacaa aataaaataa 33432 agttcaagtg ttttattgat tcaacagttt tacaggattcgagcagttat ttttcctcca 33492 ccctcccagg acatggaata caccaccctc tccccccgcacagccttgaa catctgaatg 33552 ccattggtga tggacatgct tttggtctcc acgttccacacagtttcaga gcgagccagt 33612 ctcgggtcgg tcagggagat gaaaccctcc gggcactcccgcatctgcac ctcacagctc 33672 aacagctgag gattgtcctc ggtggtcggg atcacggttatctggaagaa gcagaagagc 33732 ggcggtggga atcatagtcc gcgaacggga tcggccggtggtgtcgcatc aggccccgca 33792 gcagtcgctg tcgccgccgc tccgtcaagc tgctgctcagggggtccggg tccagggact 33852 ccctcagcat gatgcccacg gccctcagca tcagtcgtctggtgcggcgg gcgcagcagc 33912 gcatgcggat ctcgctcagg tcgctgcagt acgtgcaacacaggaccacc aggttgttca 33972 acagtccata gttcaacacg ctccagccga aactcatcgcgggaaggatg ctacccacgt 34032 ggccgtcgta ccagatcctc aggtaaatca agtggcgccccctccagaac acgctgccca 34092 tgtacatgat ctccttgggc atgtggcggt tcaccacctcccggtaccac atcaccctct 34152 ggttgaacat gcagccccgg atgatcctgc ggaaccacagggccagcacc gccccgcccg 34212 ccatgcagcg aagagacccc gggtcccgac aatggcaatggaggacccac cgctcgtacc 34272 cgtggatcat ctgggagctg aacaagtcta tgttggcacagcacaggcat atgctcatgc 34332 atctcttcag cactctcagc tcctcggggg tcaaaaccatatcccagggc acggggaact 34392 cttgcaggac agcgaacccc gcagaacagg gcaatcctcgcacataactt acattgtgca 34452 tggacagggt atcgcaatca ggcagcaccg ggtgatcctccaccagagaa gcgcgggtct 34512 cggtctcctc acagcgtggt aagggggccg gccgatacgggtgatggcgg gacgcggctg 34572 atcgtgttcg cgaccgtgtt atgatgcagt tgctttcggacattttcgta cttgctgtag 34632 cagaacctgg tccgggcgct gcacaccgat cgccggcggcggtcccggcg cttggaacgc 34692 tcggtgttga agttgtaaaa cagccactct ctcagaccgtgcagcagatc tagggcctca 34752 ggagtgatga agatcccatc atgcctgatg gctctaatcacatcgaccac cgtggaatgg 34812 gccagaccca gccagatgat gcaattttgt tgggtttcggtgacggcggg ggagggaaga 34872 acaggaagaa ccatgattaa cttttaatcc aaacggtctcggagcacttc aaaatgaaga 34932 tcgcggagat ggcacctctc gcccccgctg tgttggtggaaaataacagc caggtcaaag 34992 gtgatacggt tctcgagatg ttccacggtg gcttccagcaaagcctccac gcgcacatcc 35052 agaaacaaga caatagcgaa agcgggaggg ttctctaattcctcaatcat catgttacac 35112 tcctgcacca tccccagata attttcattt ttccagccttgaatgattcg aactagttcc 35172 tgaggtaaat ccaagccagc catgataaag agctcgcgcagagcgccctc caccggcatt 35232 cttaagcaca ccctcataat tccaagatat tctgctcctggttcacctgc agcagattga 35292 caagcggaat atcaaaatct ctgccgcgat ccctaagctcctccctcagc aataactgta 35352 agtactcttt catatcctct ccgaaatttt tagccataggaccaccagga ataagattag 35412 ggcaagccac agtacagata aaccgaagtc ctccccagtgagcattgcca aatgcaagac 35472 tgctataagc atgctggcta gacccggtga tatcttccagataactggac agaaaatcgc 35532 ccaggcaatt tttaagaaaa tcaacaaaag aaaaatcctccaggtgcacg tttagagcct 35592 cgggaacaac gatggagtaa atgcaagcgg tgcgttccagcatggttagt tagctgatct 35652 gtagaaaaaa acaaaaatga acattaaacc atgctagcctggcgaacagg tgggtaaatc 35712 gttctctcca gcaccaggca ggccacgggg tctccggcacgaccctcgta aaaattgtcg 35772 ctatgattga aaaccatcac agagagacgt tcccggtggccggcgtgaat gattcgacaa 35832 gatgaataca cccccggaac attggcgtcc gcgagtgaaaaaaagcgccc aaggaagcaa 35892 taaggcacta caatgctcag tctcaagtcc agcaaagcgatgccatgcgg atgaagcaca 35952 aaattctcag gtgcgtacaa aatgtaatta ctcccctcctgcacaggcag caaagccccc 36012 gatccctcca ggtacacata caaagcctca gcgtccatagcttaccgagc agcagcacac 36072 aacaggcgca agagtcagag aaaggctgag ctctaacctgtccacccgct ctctgctcaa 36132 tatatagccc agatctacac tgacgtaaag gccaaagtctaaaaataccc gccaaataat 36192 cacacacgcc cagcacacgc ccagaaaccg gtgacacactcaaaaaaata cgcgcacttc 36252 ctcaaacgcc caaactgccg tcatttccgg gttcccacgctacgtcatca aaattcgact 36312 ttcaaattcc gtcgaccgtt aaaaacgtcg cccgccccgcccctaacggt cgccgctccc 36372 gcagccaatc accgccccgc atccccaaat tcaaatacctcatttgcata ttaacgcgca 36432 ccaaaagttt gaggtatatt attgatgatg 36462 2 530PRT chimpanzee adenovirus serotype Pan5 2 Met Met Arg Arg Val Tyr ProGlu Gly Pro Pro Pro Ser Tyr Glu Ser 1 5 10 15 Val Met Gln Gln Ala ValAla Ala Ala Met Gln Pro Pro Leu Glu Ala 20 25 30 Pro Tyr Val Pro Pro ArgTyr Leu Ala Pro Thr Glu Gly Arg Asn Ser 35 40 45 Ile Arg Tyr Ser Glu LeuAla Pro Leu Tyr Asp Thr Thr Arg Leu Tyr 50 55 60 Leu Val Asp Asn Lys SerAla Asp Ile Ala Ser Leu Asn Tyr Gln Asn 65 70 75 80 Asp His Ser Asn PheLeu Thr Thr Val Val Gln Asn Asn Asp Phe Thr 85 90 95 Pro Thr Glu Ala SerThr Gln Thr Ile Asn Phe Asp Glu Arg Ser Arg 100 105 110 Trp Gly Gly GlnLeu Lys Thr Ile Met His Thr Asn Met Pro Asn Val 115 120 125 Asn Glu PheMet Tyr Ser Asn Lys Phe Lys Ala Arg Val Met Val Ser 130 135 140 Arg LysThr Pro Asn Gly Val Thr Val Thr Asp Gly Ser Gln Asp Glu 145 150 155 160Leu Thr Tyr Glu Trp Val Glu Phe Glu Leu Pro Glu Gly Asn Phe Ser 165 170175 Val Thr Met Thr Ile Asp Leu Met Asn Asn Ala Ile Ile Asp Asn Tyr 180185 190 Leu Ala Val Gly Arg Gln Asn Gly Val Leu Glu Ser Asp Ile Gly Val195 200 205 Lys Phe Asp Thr Arg Asn Phe Arg Leu Gly Trp Asp Pro Val ThrGlu 210 215 220 Leu Val Met Pro Gly Val Tyr Thr Asn Glu Ala Phe His ProAsp Ile 225 230 235 240 Val Leu Leu Pro Gly Cys Gly Val Asp Phe Thr GluSer Arg Leu Ser 245 250 255 Asn Leu Leu Gly Ile Arg Lys Arg Gln Pro PheGln Glu Gly Phe Gln 260 265 270 Ile Leu Tyr Glu Asp Leu Glu Gly Gly AsnIle Pro Ala Leu Leu Asp 275 280 285 Val Asp Ala Tyr Glu Lys Ser Lys GluAsp Ser Ala Ala Ala Ala Thr 290 295 300 Ala Ala Val Ala Thr Ala Ser ThrGlu Val Arg Gly Asp Asn Phe Ala 305 310 315 320 Ser Ala Ala Thr Leu AlaAla Ala Glu Ala Ala Glu Thr Glu Ser Lys 325 330 335 Ile Val Ile Gln ProVal Glu Lys Asp Ser Lys Glu Arg Ser Tyr Asn 340 345 350 Val Leu Ala AspLys Lys Asn Thr Ala Tyr Arg Ser Trp Tyr Leu Ala 355 360 365 Tyr Asn TyrGly Asp Pro Glu Lys Gly Val Arg Ser Trp Thr Leu Leu 370 375 380 Thr ThrSer Asp Val Thr Cys Gly Val Glu Gln Val Tyr Trp Ser Leu 385 390 395 400Pro Asp Met Met Gln Asp Pro Val Thr Phe Arg Ser Thr Arg Gln Val 405 410415 Ser Asn Tyr Pro Val Val Gly Ala Glu Leu Leu Pro Val Tyr Ser Lys 420425 430 Ser Phe Phe Asn Glu Gln Ala Val Tyr Ser Gln Gln Leu Arg Ala Phe435 440 445 Thr Ser Leu Thr His Val Phe Asn Arg Phe Pro Glu Asn Gln IleLeu 450 455 460 Val Arg Pro Pro Ala Pro Thr Ile Thr Thr Val Ser Glu AsnVal Pro 465 470 475 480 Ala Leu Thr Asp His Gly Thr Leu Pro Leu Arg SerSer Ile Arg Gly 485 490 495 Val Gln Arg Val Thr Val Thr Asp Ala Arg ArgArg Thr Cys Pro Tyr 500 505 510 Val Tyr Lys Ala Leu Gly Val Val Ala ProArg Val Leu Ser Ser Arg 515 520 525 Thr Phe 530 3 933 PRT chimpanzeeadenovirus serotype Pan5 3 Met Ala Thr Pro Ser Met Leu Pro Gln Trp AlaTyr Met His Ile Ala 1 5 10 15 Gly Gln Asp Ala Ser Glu Tyr Leu Ser ProGly Leu Val Gln Phe Ala 20 25 30 Arg Ala Thr Asp Thr Tyr Phe Ser Leu GlyAsn Lys Phe Arg Asn Pro 35 40 45 Thr Val Ala Pro Thr His Asp Val Thr ThrAsp Arg Ser Gln Arg Leu 50 55 60 Thr Leu Arg Phe Val Pro Val Asp Arg GluAsp Asn Thr Tyr Ser Tyr 65 70 75 80 Lys Val Arg Tyr Thr Leu Ala Val GlyAsp Asn Arg Val Leu Asp Met 85 90 95 Ala Ser Thr Tyr Phe Asp Ile Arg GlyVal Leu Asp Arg Gly Pro Ser 100 105 110 Phe Lys Pro Tyr Ser Gly Thr AlaTyr Asn Ser Leu Ala Pro Lys Gly 115 120 125 Ala Pro Asn Thr Cys Gln TrpThr Tyr Lys Ala Asp Gly Asp Thr Gly 130 135 140 Thr Glu Lys Thr Tyr ThrTyr Gly Asn Ala Pro Val Gln Gly Ile Ser 145 150 155 160 Ile Thr Lys AspGly Ile Gln Leu Gly Thr Asp Thr Asp Asp Gln Pro 165 170 175 Ile Tyr AlaAsp Lys Thr Tyr Gln Pro Glu Pro Gln Val Gly Asp Ala 180 185 190 Glu TrpHis Asp Ile Thr Gly Thr Asp Glu Lys Tyr Gly Gly Arg Ala 195 200 205 LeuLys Pro Asp Thr Lys Met Lys Pro Cys Tyr Gly Ser Phe Ala Lys 210 215 220Pro Thr Asn Lys Glu Gly Gly Gln Ala Asn Val Lys Thr Glu Thr Gly 225 230235 240 Gly Thr Lys Glu Tyr Asp Ile Asp Met Ala Phe Phe Asp Asn Arg Ser245 250 255 Ala Ala Ala Ala Gly Leu Ala Pro Glu Ile Val Leu Tyr Thr GluAsn 260 265 270 Val Asp Leu Glu Thr Pro Asp Thr His Ile Val Tyr Lys AlaGly Thr 275 280 285 Asp Asp Ser Ser Ser Ser Ile Asn Leu Gly Gln Gln SerMet Pro Asn 290 295 300 Arg Pro Asn Tyr Ile Gly Phe Arg Asp Asn Phe IleGly Leu Met Tyr 305 310 315 320 Tyr Asn Ser Thr Gly Asn Met Gly Val LeuAla Gly Gln Ala Ser Gln 325 330 335 Leu Asn Ala Val Val Asp Leu Gln AspArg Asn Thr Glu Leu Ser Tyr 340 345 350 Gln Leu Leu Leu Asp Ser Leu GlyAsp Arg Thr Arg Tyr Phe Ser Met 355 360 365 Trp Asn Gln Ala Val Asp SerTyr Asp Pro Asp Val Arg Ile Ile Glu 370 375 380 Asn His Gly Val Glu AspGlu Leu Pro Asn Tyr Cys Phe Pro Leu Asp 385 390 395 400 Ala Val Gly ArgThr Asp Thr Tyr Gln Gly Ile Lys Ala Asn Gly Ala 405 410 415 Asp Gln ThrThr Trp Thr Lys Asp Asp Thr Val Asn Asp Ala Asn Glu 420 425 430 Leu GlyLys Gly Asn Pro Phe Ala Met Glu Ile Asn Ile Gln Ala Asn 435 440 445 LeuTrp Arg Asn Phe Leu Tyr Ala Asn Val Ala Leu Tyr Leu Pro Asp 450 455 460Ser Tyr Lys Tyr Thr Pro Ala Asn Ile Thr Leu Pro Thr Asn Thr Asn 465 470475 480 Thr Tyr Asp Tyr Met Asn Gly Arg Val Val Ala Pro Ser Leu Val Asp485 490 495 Ala Tyr Ile Asn Ile Gly Ala Arg Trp Ser Leu Asp Pro Met AspAsn 500 505 510 Val Asn Pro Phe Asn His His Arg Asn Ala Gly Leu Arg TyrArg Ser 515 520 525 Met Leu Leu Gly Asn Gly Arg Tyr Val Pro Phe His IleGln Val Pro 530 535 540 Gln Lys Phe Phe Ala Ile Lys Ser Leu Leu Leu LeuPro Gly Ser Tyr 545 550 555 560 Thr Tyr Glu Trp Asn Phe Arg Lys Asp ValAsn Met Ile Leu Gln Ser 565 570 575 Ser Leu Gly Asn Asp Leu Arg Thr AspGly Ala Ser Ile Ala Phe Thr 580 585 590 Ser Ile Asn Leu Tyr Ala Thr PhePhe Pro Met Ala His Asn Thr Ala 595 600 605 Ser Thr Leu Glu Ala Met LeuArg Asn Asp Thr Asn Asp Gln Ser Phe 610 615 620 Asn Asp Tyr Leu Ser AlaAla Asn Met Leu Tyr Pro Ile Pro Ala Asn 625 630 635 640 Ala Thr Asn ValPro Ile Ser Ile Pro Ser Arg Asn Trp Ala Ala Phe 645 650 655 Arg Gly TrpSer Phe Thr Arg Leu Lys Thr Arg Glu Thr Pro Ser Leu 660 665 670 Gly SerGly Phe Asp Pro Tyr Phe Val Tyr Ser Gly Ser Ile Pro Tyr 675 680 685 LeuAsp Gly Thr Phe Tyr Leu Asn His Thr Phe Lys Lys Val Ser Ile 690 695 700Thr Phe Asp Ser Ser Val Ser Trp Pro Gly Asn Asp Arg Leu Leu Thr 705 710715 720 Pro Asn Glu Phe Glu Ile Lys Arg Thr Val Asp Gly Glu Gly Tyr Asn725 730 735 Val Ala Gln Cys Asn Met Thr Lys Asp Trp Phe Leu Val Gln MetLeu 740 745 750 Ala His Tyr Asn Ile Gly Tyr Gln Gly Phe Tyr Val Pro GluGly Tyr 755 760 765 Lys Asp Arg Met Tyr Ser Phe Phe Arg Asn Phe Gln ProMet Ser Arg 770 775 780 Gln Val Val Asp Glu Val Asn Tyr Lys Asp Tyr GlnAla Val Thr Leu 785 790 795 800 Ala Tyr Gln His Asn Asn Ser Gly Phe ValGly Tyr Leu Ala Pro Thr 805 810 815 Met Arg Gln Gly Gln Pro Tyr Pro AlaAsn Tyr Pro Tyr Pro Leu Ile 820 825 830 Gly Lys Ser Ala Val Ala Ser ValThr Gln Lys Lys Phe Leu Cys Asp 835 840 845 Arg Val Met Trp Arg Ile ProPhe Ser Ser Asn Phe Met Ser Met Gly 850 855 860 Ala Leu Thr Asp Leu GlyGln Asn Met Leu Tyr Ala Asn Ser Ala His 865 870 875 880 Ala Leu Asp MetAsn Phe Glu Val Asp Pro Met Asp Glu Ser Thr Leu 885 890 895 Leu Tyr ValVal Phe Glu Val Phe Asp Val Val Arg Val His Gln Pro 900 905 910 His ArgGly Val Ile Glu Ala Val Tyr Leu Arg Thr Pro Phe Ser Ala 915 920 925 GlyAsn Ala Thr Thr 930 4 445 PRT chimpanzee adenovirus serotype Pan5 4 MetSer Lys Lys Arg Val Arg Val Asp Asp Asp Phe Asp Pro Val Tyr 1 5 10 15Pro Tyr Asp Ala Asp Asn Ala Pro Thr Val Pro Phe Ile Asn Pro Pro 20 25 30Phe Val Ser Ser Asp Gly Phe Gln Glu Lys Pro Leu Gly Val Leu Ser 35 40 45Leu Arg Leu Ala Asp Pro Val Thr Thr Lys Asn Gly Glu Ile Thr Leu 50 55 60Lys Leu Gly Asp Gly Val Asp Leu Asp Ser Ser Gly Lys Leu Ile Ser 65 70 7580 Asn Thr Ala Thr Lys Ala Ala Ala Pro Leu Ser Phe Ser Asn Asn Thr 85 9095 Ile Ser Leu Asn Met Asp Thr Pro Phe Tyr Asn Asn Asn Gly Lys Leu 100105 110 Gly Met Lys Val Thr Ala Pro Leu Lys Ile Leu Asp Thr Asp Leu Leu115 120 125 Lys Thr Leu Val Val Ala Tyr Gly Gln Gly Leu Gly Thr Asn ThrThr 130 135 140 Gly Ala Leu Val Ala Gln Leu Ala Ser Pro Leu Ala Phe AspSer Asn 145 150 155 160 Ser Lys Ile Ala Leu Asn Leu Gly Asn Gly Pro LeuLys Val Asp Ala 165 170 175 Asn Arg Leu Asn Ile Asn Cys Asn Arg Gly LeuTyr Val Thr Thr Thr 180 185 190 Lys Asp Ala Leu Glu Ala Asn Ile Ser TrpAla Asn Ala Met Thr Phe 195 200 205 Ile Gly Asn Ala Met Gly Val Asn IleAsp Thr Gln Lys Gly Leu Gln 210 215 220 Phe Gly Thr Thr Ser Thr Val AlaAsp Val Lys Asn Ala Tyr Pro Ile 225 230 235 240 Gln Ile Lys Leu Gly AlaGly Leu Thr Phe Asp Ser Thr Gly Ala Ile 245 250 255 Val Ala Trp Asn LysAsp Asp Asp Lys Leu Thr Leu Trp Thr Thr Ala 260 265 270 Asp Pro Ser ProAsn Cys His Ile Tyr Ser Glu Lys Asp Ala Lys Leu 275 280 285 Thr Leu CysLeu Thr Lys Cys Gly Ser Gln Ile Leu Gly Thr Val Ser 290 295 300 Leu IleAla Val Asp Thr Gly Ser Leu Asn Pro Ile Thr Gly Thr Val 305 310 315 320Thr Thr Ala Leu Val Ser Leu Lys Phe Asp Ala Asn Gly Val Leu Gln 325 330335 Ser Ser Ser Thr Leu Asp Ser Asp Tyr Trp Asn Phe Arg Gln Gly Asp 340345 350 Val Thr Pro Ala Glu Ala Tyr Thr Asn Ala Ile Gly Phe Met Pro Asn355 360 365 Leu Lys Ala Tyr Pro Lys Asn Thr Ser Gly Ala Ala Lys Ser HisIle 370 375 380 Val Gly Lys Val Tyr Leu His Gly Asp Thr Gly Lys Pro LeuAsp Leu 385 390 395 400 Ile Ile Thr Phe Asn Glu Thr Ser Asp Glu Ser CysThr Tyr Cys Ile 405 410 415 Asn Phe Gln Trp Gln Trp Gly Ala Asp Gln TyrLys Asn Glu Thr Leu 420 425 430 Ala Val Ser Ser Phe Thr Phe Ser Tyr IleAla Lys Glu 435 440 445 5 36604 DNA chimpanzee adenovirus serotype Pan6CDS (13878)..(15467) L2 Penton 5 catcatcaat aatatacctc aaacttttggtgcgcgttaa tatgcaaatg agctgtttga 60 atttggggag ggaggaaggt gattggctgcgggagcggcg accgttaggg gcggggcggg 120 tgacgttttg atgacgtggc tatgaggcggagccggtttg caagttctcg tgggaaaagt 180 gacgtcaaac gaggtgtggt ttgaacacggaaatactcaa ttttcccgcg ctctctgaca 240 ggaaatgagg tgtttctggg cggatgcaagtgaaaacggg ccattttcgc gcgaaaactg 300 aatgaggaag tgaaaatctg agtaatttcgcgtttatggc agggaggagt atttgccgag 360 ggccgagtag actttgaccg attacgtgggggtttcgatt accgtatttt tcacctaaat 420 ttccgcgtac ggtgtcaaag tccggtgtttttacgtaggc gtcagctgat cgccagggta 480 tttaaacctg cgctctctag tcaagaggccactcttgagt gccagcgagt agagttttct 540 cctccgcgcc gcgagtcaga tctacactttgaaagatgag gcacctgaga gacctgcccg 600 gtaatgtttt cctggctact gggaacgagattctggaatt ggtggtggac gccatgatgg 660 gtgacgaccc tccagagccc cctaccccatttgaggcgcc ttcgctgtac gatttgtatg 720 atctggaggt ggatgtgccc gagagcgaccctaacgagga ggcggtgaat gatttgttta 780 gcgatgccgc gctgctggct gccgagcaggctaatacgga ctctggctca gacagcgatt 840 cctctctcca taccccgaga cccggcagaggtgagaaaaa gatccccgag cttaaagggg 900 aagagctcga cctgcgctgc tatgaggaatgcttgcctcc gagcgatgat gaggaggacg 960 aggaggcgat tcgagctgcg gtgaaccagggagtgaaaac tgcgggcgag agctttagcc 1020 tggactgtcc tactctgccc ggacacggctgtaagtcttg tgaatttcat cgcatgaata 1080 ctggagataa gaatgtgatg tgtgccctgtgctatatgag agcttacaac cattgtgttt 1140 acagtaagtg tgattaactt tagttgggaaggcagagggt gactgggtgc tgactggttt 1200 atttatgtat atgttttttt atgtgtaggtcccgtctctg acgtagatga gacccccact 1260 tcagagtgca tttcatcacc cccagaaattggcgaggaac cgcccgaaga tattattcat 1320 agaccagttg cagtgagagt caccgggcggagagcagctg tggagagttt ggatgacttg 1380 ctacagggtg gggatgaacc tttggacttgtgtacccgga aacgccccag gcactaagtg 1440 ccacacatgt gtgtttactt aaggtgatgtcagtatttat agggtgtgga gtgcaataaa 1500 atccgtgttg actttaagtg cgtgttttatgactcagggg tggggactgt gggtatataa 1560 gcaggtgcag acctgtgtgg tcagttcagagcaggactca tggagatctg gactgtcttg 1620 gaagactttc accagactag acagttgctagagaactcat cggagggagt ctcttacctg 1680 tggagattct gcttcggtgg gcctctagctaagctagtct atagggccaa acaggattat 1740 aaggaacaat ttgaggatat tttgagagagtgtcctggta tttttgactc tctcaacttg 1800 ggccatcagt ctcactttaa ccagagtattctgagagccc ttgacttttc tactcctggc 1860 agaactaccg ccgcggtagc cttttttgcctttattcttg acaaatggag tcaagaaacc 1920 catttcagca gggattaccg tctggactgcttagcagtag ctttgtggag aacatggagg 1980 tgccagcgcc tgaatgcaat ctccggctacttgccagtac agccggtaga cacgctgagg 2040 atcctgagtc tccagtcacc ccaggaacaccaacgccgcc agcagccgca gcaggagcag 2100 cagcaagagg aggaccgaga agagaacccgagagccggtc tggaccctcc ggtggcggag 2160 gaggaggagt agctgacttg tttcccgagctgcgccgggt gctgactagg tcttccagtg 2220 gacgggagag ggggattaag cgggagaggcatgaggagac tagccacaga actgaactga 2280 ctgtcagtct gatgagccgc aggcgcccagaatcggtgtg gtggcatgag gtgcagtcgc 2340 aggggataga tgaggtctcg gtgatgcatgagaaatattc cctagaacaa gtcaagactt 2400 gttggttgga gcccgaggat gattgggaggtagccatcag gaattatgcc aagctggctc 2460 tgaagccaga caagaagtac aagattaccaaactgattaa tatcagaaat tcctgctaca 2520 tttcagggaa tggggccgag gtggagatcagtacccagga gagggtggcc ttcagatgtt 2580 gtatgatgaa tatgtacccg ggggtggtgggcatggaggg agtcaccttt atgaacacga 2640 ggttcagggg tgatgggtat aatggggtggtctttatggc caacaccaag ctgacagtgc 2700 acggatgctc cttctttggc ttcaataacatgtgcatcga ggcctggggc agtgtttcag 2760 tgaggggatg cagcttttca gccaactggatgggggtcgt gggcagaacc aagagcaagg 2820 tgtcagtgaa gaaatgcctg ttcgagaggtgccacctggg ggtgatgagc gagggcgaag 2880 ccaaagtcaa acactgcgcc tctaccgagacgggctgctt tgtgctgatc aagggcaatg 2940 cccaagtcaa gcataacatg atctgtggggcctcggatga gcgcggctac cagatgctga 3000 cctgcgccgg tgggaacagc catatgctggccaccgtgca tgtggcctcg cacccccgca 3060 agacatggcc cgagttcgag cacaacgtcatgacccgctg caatgtgcac ctgggctccc 3120 gccgaggcat gttcatgccc taccagtgcaacatgcaatt tgtgaaggtg ctgctggagc 3180 ccgatgccat gtccagagtg agcctgacgggggtgtttga catgaatgtg gagctgtgga 3240 aaattctgag atatgatgaa tccaagaccaggtgccgggc ctgcgaatgc ggaggcaagc 3300 acgccaggct tcagcccgtg tgtgtggaggtgacggagga cctgcgaccc gatcatttgg 3360 tgttgtcctg caacgggacg gagttcggctccagcgggga agaatctgac tagagtgagt 3420 agtgtttggg gctgggtgtg agcctgcatgaggggcagaa tgactaaaat ctgtggtttt 3480 ctgtgtgttg cagcagcatg agcggaagcgcctcctttga gggaggggta ttcagccctt 3540 atctgacggg gcgtctcccc tcctgggcgggagtgcgtca gaatgtgatg ggatccacgg 3600 tggacggccg gcccgtgcag cccgcgaactcttcaaccct gacctacgcg accctgagct 3660 cctcgtccgt ggacgcagct gccgccgcagctgctgcttc cgccgccagc gccgtgcgcg 3720 gaatggccct gggcgccggc tactacagctctctggtggc caactcgagt tccaccaata 3780 atcccgccag cctgaacgag gagaagctgctgctgctgat ggcccagctc gaggccctga 3840 cccagcgcct gggcgagctg acccagcaggtggctcagct gcaggcggag acgcgggccg 3900 cggttgccac ggtgaaaacc aaataaaaaatgaatcaata aataaacgga gacggttgtt 3960 gattttaaca cagagtcttg aatctttatttgatttttcg cgcgcggtag gccctggacc 4020 accggtctcg atcattgagc acccggtggatcttttccag gacccggtag aggtgggctt 4080 ggatgttgag gtacatgggc atgagcccgtcccgggggtg gaggtagctc cattgcaggg 4140 cctcgtgctc ggggatggtg ttgtaaatcacccagtcata gcaggggcgc agggcgtggt 4200 gctgcacgat gtccttgagg aggagactgatggccacggg cagccccttg gtgtaggtgt 4260 tgacgaacct gttgagctgg gagggatgcatgcgggggga gatgagatgc atcttggcct 4320 ggatcttgag attggcgatg ttcccgcccagatcccgccg ggggttcatg ttgtgcagga 4380 ccaccagcac ggtgtatccg gtgcacttggggaatttgtc atgcaacttg gaagggaagg 4440 cgtgaaagaa tttggagacg cccttgtgaccgcccaggtt ttccatgcac tcatccatga 4500 tgatggcgat gggcccgtgg gcggcggcctgggcaaagac gtttcggggg tcggacacat 4560 cgtagttgtg gtcctgggtg agctcgtcataggccatttt aatgaatttg gggcggaggg 4620 tgcccgactg ggggacgaag gtgccctcgatcccgggggc gtagttgccc tcgcagatct 4680 gcatctccca ggccttgagc tcggagggggggatcatgtc cacctgcggg gcgatgaaaa 4740 aaacggtttc cggggcgggg gagatgagctgggccgaaag caggttccgg agcagctggg 4800 acttgccgca accggtgggg ccgtagatgaccccgatgac cggctgcagg tggtagttga 4860 gggagagaca gctgccgtcc tcgcggaggaggggggccac ctcgttcatc atctcgcgca 4920 catgcatgtt ctcgcgcacg agttccgccaggaggcgctc gccccccagc gagaggagct 4980 cttgcagcga ggcgaagttt ttcagcggcttgagtccgtc ggccatgggc attttggaga 5040 gggtctgttg caagagttcc agacggtcccagagctcggt gatgtgctct agggcatctc 5100 gatccagcag acctcctcgt ttcgcgggttggggcgactg cgggagtagg gcaccaggcg 5160 atgggcgtcc agcgaggcca gggtccggtccttccagggc cgcagggtcc gcgtcagcgt 5220 ggtctccgtc acggtgaagg ggtgcgcgccgggctgggcg cttgcgaggg tgcgcttcag 5280 gctcatccgg ctggtcgaga accgctcccggtcggcgccc tgcgcgtcgg ccaggtagca 5340 attgagcatg agttcgtagt tgagcgcctcggccgcgtgg cccttggcgc ggagcttacc 5400 tttggaagtg tgtccgcaga cgggacagaggagggacttg agggcgtaga gcttgggggc 5460 gaggaagacg gactcggggg cgtaggcgtccgcgccgcag ctggcgcaga cggtctcgca 5520 ctccacgagc caggtgaggt cggggcggttggggtcaaaa acgaggtttc ctccgtgctt 5580 tttgatgcgt ttcttacctc tggtctccatgagctcgtgt ccccgctggg tgacaaagag 5640 gctgtccgtg tccccgtaga ccgactttatgggccggtcc tcgagcgggg tgccgcggtc 5700 ctcgtcgtag aggaaccccg cccactccgagacgaaggcc cgggtccagg ccagcacgaa 5760 ggaggccacg tgggaggggt agcggtcgttgtccaccagc gggtccacct tctccagggt 5820 atgcaagcac atgtccccct cgtccacatccaggaaggtg attggcttgt aagtgtaggc 5880 cacgtgaccg ggggtcccgg ccgggggggtataaaagggg gcgggcccct gctcgtcctc 5940 actgtcttcc ggatcgctgt ccaggagcgccagctgttgg ggtaggtatt ccctctcgaa 6000 ggcgggcatg acctcggcac tcaggttgtcagtttctaga aacgaggagg atttgatatt 6060 gacggtgccg ttggagacgc ctttcatgagcccctcgtcc atttggtcag aaaagacgat 6120 ctttttgttg tcgagcttgg tggcgaaggagccgtagagg gcgttggaga gcagcttggc 6180 gatggagcgc atggtctggt tcttttccttgtcggcgcgc tccttggcgg cgatgttgag 6240 ctgcacgtac tcgcgcgcca cgcacttccattcggggaag acggtggtga gctcgtcggg 6300 cacgattctg acccgccagc cgcggttgtgcagggtgatg aggtccacgc tggtggccac 6360 ctcgccgcgc aggggctcgt tggtccagcagaggcgcccg cccttgcgcg agcagaaggg 6420 gggcagcggg tccagcatga gctcgtcgggggggtcggcg tccacggtga agatgccggg 6480 caggagctcg gggtcgaagt agctgatgcaggtgcccaga ttgtccagcg ccgcttgcca 6540 gtcgcgcacg gccagcgcgc gctcgtaggggctgaggggc gtgccccagg gcatggggtg 6600 cgtgagcgcg gaggcgtaca tgccgcagatgtcgtagacg tagaggggct cctcgaggac 6660 gccgatgtag gtggggtagc agcgccccccgcggatgctg gcgcgcacgt agtcgtacag 6720 ctcgtgcgag ggcgcgagga gccccgtgccgaggttggag cgttgcggct tttcggcgcg 6780 gtagacgatc tggcggaaga tggcgtgggagttggaggag atggtgggcc tttggaagat 6840 gttgaagtgg gcgtggggca ggccgaccgagtccctgatg aagtgggcgt aggagtcctg 6900 cagcttggcg acgagctcgg cggtgacgaggacgtccagg gcgcagtagt cgagggtctc 6960 ttggatgatg tcatacttga gctggcccttctgcttccac agctcgcggt tgagaaggaa 7020 ctcttcgcgg tccttccagt actcttcgagggggaacccg tcctgatcgg cacggtaaga 7080 gcccaccatg tagaactggt tgacggccttgtaggcgcag cagcccttct ccacggggag 7140 ggcgtaagct tgcgcggcct tgcgcagggaggtgtgggtg agggcgaagg tgtcgcgcac 7200 catgaccttg aggaactggt gcttgaagtcgaggtcgtcg cagccgccct gctcccagag 7260 ttggaagtcc gtgcgcttct tgtaggcggggttaggcaaa gcgaaagtaa catcgttgaa 7320 gaggatcttg cccgcgcggg gcatgaagttgcgagtgatg cggaaaggct ggggcacctc 7380 ggcccggttg ttgatgacct gggcggcgaggacgatctcg tcgaagccgt tgatgttgtg 7440 cccgacgatg tagagttcca cgaatcgcgggcggcccttg acgtggggca gcttcttgag 7500 ctcgtcgtag gtgagctcgg cggggtcgctgagcccgtgc tgctcgaggg cccagtcggc 7560 gacgtggggg ttggcgctga ggaaggaagtccagagatcc acggccaggg cggtctgcaa 7620 gcggtcccgg tactgacgga actgttggcccacggccatt ttttcggggg tgacgcagta 7680 gaaggtgcgg gggtcgccgt gccagcggtcccacttgagc tggagggcga ggtcgtgggc 7740 gagctcgacg agcggcgggt ccccggagagtttcatgacc agcatgaagg ggacgagctg 7800 cttgccgaag gaccccatcc aggtgtaggtttccacatcg taggtgagga agagcctttc 7860 ggtgcgagga tgcgagccga tggggaagaactggatctcc tgccaccagt tggaggaatg 7920 gctgttgatg tgatggaagt agaaatgccgacggcgcgcc gagcactcgt gcttgtgttt 7980 atacaagcgt ccgcagtgct cgcaacgctgcacgggatgc acgtgctgca cgagctgtac 8040 ctgggttcct ttggcgagga atttcagtgggcagtggagc gctggcggct gcatctcgtg 8100 ctgtactacg tcttggccat cggcgtggccatcgtctgcc tcgatggtgg tcatgctgac 8160 gagcccgcgc gggaggcagg tccagacctcggctcggacg ggtcggagag cgaggacgag 8220 ggcgcgcagg ccggagctgt ccagggtcctgagacgctgc ggagtcaggt cagtgggcag 8280 cggcggcgcg cggttgactt gcaggagcttttccagggcg cgcgggaggt ccagatggta 8340 cttgatctcc acggcgccgt tggtggctacgtccacggct tgcagggtgc cgtgcccctg 8400 gggcgccacc accgtgcccc gtttcttcttgggcgctgct tccatgtcgg tcagaagcgg 8460 cggcgaggac gcgcgccggg cggcaggggcggctcggggc ccggaggcag gggcggcagg 8520 ggcacgtcgg cgccgcgcgc gggcaggttctggtactgcg cccggagaag actggcgtga 8580 gcgacgacgc gacggttgac gtcctggatctgacgcctct gggtgaaggc cacgggaccc 8640 gtgagtttga acctgaaaga gagttcgacagaatcaatct cggtatcgtt gacggcggcc 8700 tgccgcagga tctcttgcac gtcgcccgagttgtcctggt aggcgatctc ggtcatgaac 8760 tgctcgatct cctcctcctg aaggtctccgcggccggcgc gctcgacggt ggccgcgagg 8820 tcgttggaga tgcggcccat gagctgcgagaaggcgttca tgccggcctc gttccagacg 8880 cggctgtaga ccacggctcc gtcggggtcgcgcgcgcgca tgaccacctg ggcgaggttg 8940 agctcgacgt ggcgcgtgaa gaccgcgtagttgcagaggc gctggtagag gtagttgagc 9000 gtggtggcga tgtgctcggt gacgaagaagtacatgatcc agcggcggag cggcatctcg 9060 ctgacgtcgc ccagggcttc caagcgttccatggcctcgt agaagtccac ggcgaagttg 9120 aaaaactggg agttgcgcgc cgagacggtcaactcctcct ccagaagacg gatgagctcg 9180 gcgatggtgg cgcgcacctc gcgctcgaaggccccggggg gctcctcttc catctcctcc 9240 tcttcctcct ccactaacat ctcttctacttcctcctcag gaggcggtgg cgggggaggg 9300 gccctgcgtc gccggcggcg cacgggcagacggtcgatga agcgctcgat ggtctccccg 9360 cgccggcgac gcatggtctc ggtgacggcgcgcccgtcct cgcggggccg cagcatgaag 9420 acgccgccgc gcatctccag gtggccgccgggggggtctc cgttgggcag ggagagggcg 9480 ctgacgatgc atcttatcaa ttgacccgtagggactccgc gcaaggacct gagcgtctcg 9540 agatccacgg gatccgaaaa ccgctgaacgaaggcttcga gccagtcgca gtcgcaaggt 9600 aggctgagcc cggtttcttg ttcttcgggtatttggtcgg gaggcgggcg ggcgatgctg 9660 ctggtgatga agttgaagta ggcggtcctgagacggcgga tggtggcgag gagcaccagg 9720 tccttgggcc cggcttgctg gatgcgcagacggtcggcca tgccccaggc gtggtcctga 9780 cacctggcga ggtccttgta gtagtcctgcatgagccgct ccacgggcac ctcctcctcg 9840 cccgcgcggc cgtgcatgcg cgtgagcccgaacccgcgct gcggctggac gagcgccagg 9900 tcggcgacga cgcgctcggt gaggatggcctgctggatct gggtgagggt ggtctggaag 9960 tcgtcgaagt cgacgaagcg gtggtaggctccggtgttga tggtgtagga gcagttggcc 10020 atgacggacc agttgacggt ctggtggccgggtcgcacga gctcgtggta cttgaggcgc 10080 gagtaggcgc gcgtgtcgaa gatgtagtcgttgcaggcgc gcacgaggta ctggtatccg 10140 acgaggaagt gcggcggcgg ctggcggtagagcggccatc gctcggtggc gggggcgccg 10200 ggcgcgaggt cctcgagcat gaggcggtggtagccgtaga tgtacctgga catccaggtg 10260 atgccggcgg cggtggtgga ggcgcgcgggaactcgcgga cgcggttcca gatgttgcgc 10320 agcggcagga agtagttcat ggtggccgcggtctggcccg tgaggcgcgc gcagtcgtgg 10380 atgctctaga catacgggca aaaacgaaagcggtcagcgg ctcgactccg tggcctggag 10440 gctaagcgaa cgggttgggc tgcgcgtgtaccccggttcg aatctcgaat caggctggag 10500 ccgcagctaa cgtggtactg gcactcccgtctcgacccaa gcctgctaac gaaacctcca 10560 ggatacggag gcgggtcgtt ttttggccttggtcgctggt catgaaaaac tagtaagcgc 10620 ggaaagcggc cgcccgcgat ggctcgctgccgtagtctgg agaaagaatc gccagggttg 10680 cgttgcggtg tgccccggtt cgagcctcagcgctcggcgc cggccggatt ccgcggctaa 10740 cgtgggcgtg gctgccccgt cgtttccaagaccccttagc cagccgactt ctccagttac 10800 ggagcgagcc cctctttttt tttcttgtgtttttgccaga tgcatcccgt actgcggcag 10860 atgcgccccc accctccacc acaaccgcccctaccgcagc agcagcaaca gccggcgctt 10920 ctgcccccgc cccagcagca gccagccactaccgcggcgg ccgccgtgag cggagccggc 10980 gttcagtatg acctggcctt ggaagagggcgaggggctgg cgcggctggg ggcgtcgtcg 11040 ccggagcggc acccgcgcgt gcagatgaaaagggacgctc gcgaggccta cgtgcccaag 11100 cagaacctgt tcagagacag gagcggcgaggagcccgagg agatgcgcgc ctcccgcttc 11160 cacgcggggc gggagctgcg gcgcggcctggaccgaaagc gggtgctgag ggacgaggat 11220 ttcgaggcgg acgagctgac ggggatcagccccgcgcgcg cgcacgtggc cgcggccaac 11280 ctggtcacgg cgtacgagca gaccgtgaaggaggagagca acttccaaaa atccttcaac 11340 aaccacgtgc gcacgctgat cgcgcgcgaggaggtgaccc tgggcctgat gcacctgtgg 11400 gacctgctgg aggccatcgt gcagaaccccacgagcaagc cgctgacggc gcagctgttt 11460 ctggtggtgc agcacagtcg ggacaacgagacgttcaggg aggcgctgct gaatatcacc 11520 gagcccgagg gccgctggct cctggacctggtgaacattt tgcagagcat cgtggtgcag 11580 gagcgcgggc tgccgctgtc cgagaagctggcggccatca acttctcggt gctgagtctg 11640 ggcaagtact acgctaggaa gatctacaagaccccgtacg tgcccataga caaggaggtg 11700 aagatcgacg ggttttacat gcgcatgaccctgaaagtgc tgaccctgag cgacgatctg 11760 ggggtgtacc gcaacgacag gatgcaccgcgcggtgagcg ccagccgccg gcgcgagctg 11820 agcgaccagg agctgatgca cagcctgcagcgggccctga ccggggccgg gaccgagggg 11880 gagagctact ttgacatggg cgcggacctgcgctggcagc ccagccgccg ggccttggaa 11940 gctgccggcg gttcccccta cgtggaggaggtggacgatg aggaggagga gggcgagtac 12000 ctggaagact gatggcgcga ccgtatttttgctagatgca gcaacagcca ccgccgccgc 12060 ctcctgatcc cgcgatgcgg gcggcgctgcagagccagcc gtccggcatt aactcctcgg 12120 acgattggac ccaggccatg caacgcatcatggcgctgac gacccgcaat cccgaagcct 12180 ttagacagca gcctcaggcc aaccggctctcggccatcct ggaggccgtg gtgccctcgc 12240 gctcgaaccc cacgcacgag aaggtgctggccatcgtgaa cgcgctggtg gagaacaagg 12300 ccatccgcgg tgacgaggcc gggctggtgtacaacgcgct gctggagcgc gtggcccgct 12360 acaacagcac caacgtgcag acgaacctggaccgcatggt gaccgacgtg cgcgaggcgg 12420 tgtcgcagcg cgagcggttc caccgcgagtcgaacctggg ctccatggtg gcgctgaacg 12480 ccttcctgag cacgcagccc gccaacgtgccccggggcca ggaggactac accaacttca 12540 tcagcgcgct gcggctgatg gtggccgaggtgccccagag cgaggtgtac cagtcggggc 12600 cggactactt cttccagacc agtcgccagggcttgcagac cgtgaacctg agccaggctt 12660 tcaagaactt gcagggactg tggggcgtgcaggccccggt cggggaccgc gcgacggtgt 12720 cgagcctgct gacgccgaac tcgcgcctgctgctgctgct ggtggcgccc ttcacggaca 12780 gcggcagcgt gagccgcgac tcgtacctgggctacctgct taacctgtac cgcgaggcca 12840 tcggacaggc gcacgtggac gagcagacctaccaggagat cacccacgtg agccgcgcgc 12900 tgggccagga ggacccgggc aacctggaggccaccctgaa cttcctgctg accaaccggt 12960 cgcagaagat cccgccccag tacgcgctgagcaccgagga ggagcgcatc ctgcgctacg 13020 tgcagcagag cgtggggctg ttcctgatgcaggagggggc cacgcccagc gcggcgctcg 13080 acatgaccgc gcgcaacatg gagcccagcatgtacgcccg caaccgcccg ttcatcaata 13140 agctgatgga ctacttgcat cgggcggccgccatgaactc ggactacttt accaacgcca 13200 tcttgaaccc gcactggctc ccgccgcccgggttctacac gggcgagtac gacatgcccg 13260 accccaacga cgggttcctg tgggacgacgtggacagcag cgtgttctcg ccgcgtccag 13320 gaaccaatgc cgtgtggaag aaagagggcggggaccggcg gccgtcctcg gcgctgtccg 13380 gtcgcgcggg tgctgccgcg gcggtgcccgaggccgccag ccccttcccg agcctgccct 13440 tttcgctgaa cagcgtgcgc agcagcgagctgggtcggct gacgcgaccg cgcctgctgg 13500 gcgaggagga gtacctgaac gactccttgttgaggcccga gcgcgagaag aacttcccca 13560 ataacgggat agagagcctg gtggacaagatgagccgctg gaagacgtac gcgcacgagc 13620 acagggacga gccccgagct agcagcgcaggcacccgtag acgccagcgg cacgacaggc 13680 agcggggact ggtgtgggac gatgaggattccgccgacga cagcagcgtg ttggacttgg 13740 gtgggagtgg tggtaacccg ttcgctcacctgcgcccccg tatcgggcgc ctgatgtaag 13800 aatctgaaaa aataaaagac ggtactcaccaaggccatgg cgaccagcgt gcgttcttct 13860 ctgttgtttg tagtagt atg atg aggcgc gtg tac ccg gag ggt cct cct 13910 Met Met Arg Arg Val Tyr Pro GluGly Pro Pro 1 5 10 ccc tcg tac gag agc gtg atg cag cag gcg gtg gcg gcggcg atg cag 13958 Pro Ser Tyr Glu Ser Val Met Gln Gln Ala Val Ala AlaAla Met Gln 15 20 25 ccc ccg ctg gag gcg cct tac gtg ccc ccg cgg tac ctggcg cct acg 14006 Pro Pro Leu Glu Ala Pro Tyr Val Pro Pro Arg Tyr LeuAla Pro Thr 30 35 40 gag ggg cgg aac agc att cgt tac tcg gag ctg gca cccttg tac gat 14054 Glu Gly Arg Asn Ser Ile Arg Tyr Ser Glu Leu Ala ProLeu Tyr Asp 45 50 55 acc acc cgg ttg tac ctg gtg gac aac aag tcg gca gacatc gcc tcg 14102 Thr Thr Arg Leu Tyr Leu Val Asp Asn Lys Ser Ala AspIle Ala Ser 60 65 70 75 ctg aac tac cag aac gac cac agc aac ttc ctg accacc gtg gtg cag 14150 Leu Asn Tyr Gln Asn Asp His Ser Asn Phe Leu ThrThr Val Val Gln 80 85 90 aac aac gat ttc acc ccc acg gag gcc agc acc cagacc atc aac ttt 14198 Asn Asn Asp Phe Thr Pro Thr Glu Ala Ser Thr GlnThr Ile Asn Phe 95 100 105 gac gag cgc tcg cgg tgg ggc ggc cag ctg aaaacc atc atg cac acc 14246 Asp Glu Arg Ser Arg Trp Gly Gly Gln Leu LysThr Ile Met His Thr 110 115 120 aac atg ccc aac gtg aac gag ttc atg tacagc aac aag ttc aag gcg 14294 Asn Met Pro Asn Val Asn Glu Phe Met TyrSer Asn Lys Phe Lys Ala 125 130 135 cgg gtg atg gtc tcg cgc aag acc cccaac ggg gtg gat gat gat tat 14342 Arg Val Met Val Ser Arg Lys Thr ProAsn Gly Val Asp Asp Asp Tyr 140 145 150 155 gat ggt agt cag gac gag ctgacc tac gag tgg gtg gag ttt gag ctg 14390 Asp Gly Ser Gln Asp Glu LeuThr Tyr Glu Trp Val Glu Phe Glu Leu 160 165 170 ccc gag ggc aac ttc tcggtg acc atg acc atc gat ctg atg aac aac 14438 Pro Glu Gly Asn Phe SerVal Thr Met Thr Ile Asp Leu Met Asn Asn 175 180 185 gcc atc atc gac aactac ttg gcg gtg ggg cgg cag aac ggg gtg ctg 14486 Ala Ile Ile Asp AsnTyr Leu Ala Val Gly Arg Gln Asn Gly Val Leu 190 195 200 gag agc gac atcggc gtg aag ttc gac acg cgc aac ttc cgg ctg ggc 14534 Glu Ser Asp IleGly Val Lys Phe Asp Thr Arg Asn Phe Arg Leu Gly 205 210 215 tgg gac cccgtg acc gag ctg gtg atg ccg ggc gtg tac acc aac gag 14582 Trp Asp ProVal Thr Glu Leu Val Met Pro Gly Val Tyr Thr Asn Glu 220 225 230 235 gccttc cac ccc gac atc gtc ctg ctg ccc ggc tgc ggc gtg gac ttc 14630 AlaPhe His Pro Asp Ile Val Leu Leu Pro Gly Cys Gly Val Asp Phe 240 245 250acc gag agc cgc ctc agc aac ctg ctg ggc atc cgc aag cgg cag ccc 14678Thr Glu Ser Arg Leu Ser Asn Leu Leu Gly Ile Arg Lys Arg Gln Pro 255 260265 ttc cag gag ggc ttc cag atc ctg tac gag gac ctg gag ggg ggc aac14726 Phe Gln Glu Gly Phe Gln Ile Leu Tyr Glu Asp Leu Glu Gly Gly Asn270 275 280 atc ccc gcg ctc ttg gat gtc gaa gcc tac gag aaa agc aag gaggat 14774 Ile Pro Ala Leu Leu Asp Val Glu Ala Tyr Glu Lys Ser Lys GluAsp 285 290 295 agc acc gcc gcg gcg acc gca gcc gtg gcc acc gcc tct accgag gtg 14822 Ser Thr Ala Ala Ala Thr Ala Ala Val Ala Thr Ala Ser ThrGlu Val 300 305 310 315 cgg ggc gat aat ttt gct agc gct gcg gca gcg gccgag gcg gct gaa 14870 Arg Gly Asp Asn Phe Ala Ser Ala Ala Ala Ala AlaGlu Ala Ala Glu 320 325 330 acc gaa agt aag ata gtc atc cag ccg gtg gagaag gac agc aag gac 14918 Thr Glu Ser Lys Ile Val Ile Gln Pro Val GluLys Asp Ser Lys Asp 335 340 345 agg agc tac aac gtg ctc gcg gac aag aaaaac acc gcc tac cgc agc 14966 Arg Ser Tyr Asn Val Leu Ala Asp Lys LysAsn Thr Ala Tyr Arg Ser 350 355 360 tgg tac ctg gcc tac aac tac ggc gacccc gag aag ggc gtg cgc tcc 15014 Trp Tyr Leu Ala Tyr Asn Tyr Gly AspPro Glu Lys Gly Val Arg Ser 365 370 375 tgg acg ctg ctc acc acc tcg gacgtc acc tgc ggc gtg gag caa gtc 15062 Trp Thr Leu Leu Thr Thr Ser AspVal Thr Cys Gly Val Glu Gln Val 380 385 390 395 tac tgg tcg ctg ccc gacatg atg caa gac ccg gtc acc ttc cgc tcc 15110 Tyr Trp Ser Leu Pro AspMet Met Gln Asp Pro Val Thr Phe Arg Ser 400 405 410 acg cgt caa gtt agcaac tac ccg gtg gtg ggc gcc gag ctc ctg ccc 15158 Thr Arg Gln Val SerAsn Tyr Pro Val Val Gly Ala Glu Leu Leu Pro 415 420 425 gtc tac tcc aagagc ttc ttc aac gag cag gcc gtc tac tcg cag cag 15206 Val Tyr Ser LysSer Phe Phe Asn Glu Gln Ala Val Tyr Ser Gln Gln 430 435 440 ctg cgc gccttc acc tcg ctc acg cac gtc ttc aac cgc ttc ccc gag 15254 Leu Arg AlaPhe Thr Ser Leu Thr His Val Phe Asn Arg Phe Pro Glu 445 450 455 aac cagatc ctc gtc cgc ccg ccc gcg ccc acc att acc acc gtc agt 15302 Asn GlnIle Leu Val Arg Pro Pro Ala Pro Thr Ile Thr Thr Val Ser 460 465 470 475gaa aac gtt cct gct ctc aca gat cac ggg acc ctg ccg ctg cgc agc 15350Glu Asn Val Pro Ala Leu Thr Asp His Gly Thr Leu Pro Leu Arg Ser 480 485490 agt atc cgg gga gtc cag cgc gtg acc gtc act gac gcc aga cgc cgc15398 Ser Ile Arg Gly Val Gln Arg Val Thr Val Thr Asp Ala Arg Arg Arg495 500 505 acc tgc ccc tac gtc tac aag gcc ctg ggc gta gtc gcg ccg cgcgtc 15446 Thr Cys Pro Tyr Val Tyr Lys Ala Leu Gly Val Val Ala Pro ArgVal 510 515 520 ctc tcg agc cgc acc ttc taa aaaatgtcca ttctcatctcgcccagtaat 15497 Leu Ser Ser Arg Thr Phe 525 aacaccggtt ggggcctgcgcgcgcccagc aagatgtacg gaggcgctcg ccaacgctcc 15557 acgcaacacc ccgtgcgcgtgcgcgggcac ttccgcgctc cctggggcgc cctcaagggc 15617 cgcgtgcgct cgcgcaccaccgtcgacgac gtgatcgacc aggtggtggc cgacgcgcgc 15677 aactacacgc ccgccgccgcgcccgtctcc accgtggacg ccgtcatcga cagcgtggtg 15737 gccgacgcgc gccggtacgcccgcaccaag agccggcggc ggcgcatcgc ccggcggcac 15797 cggagcaccc ccgccatgcgcgcggcgcga gccttgctgc gcagggccag gcgcacggga 15857 cgcagggcca tgctcagggcggccagacgc gcggcctccg gcagcagcag cgccggcagg 15917 acccgcagac gcgcggccacggcggcggcg gcggccatcg ccagcatgtc ccgcccgcgg 15977 cgcggcaacg tgtactgggtgcgcgacgcc gccaccggtg tgcgcgtgcc cgtgcgcacc 16037 cgcccccctc gcacttgaagatgctgactt cgcgatgttg atgtgtccca gcggcgagga 16097 ggatgtccaa gcgcaaatacaaggaagaga tgctccaggt catcgcgcct gagatctacg 16157 gccccgcggc ggcggtgaaggaggaaagaa agccccgcaa actgaagcgg gtcaaaaagg 16217 acaaaaagga ggaggaagatgacggactgg tggagtttgt gcgcgagttc gccccccggc 16277 ggcgcgtgca gtggcgcgggcggaaagtga aaccggtgct gcggcccggc accacggtgg 16337 tcttcacgcc cggcgagcgttccggctccg cctccaagcg ctcctacgac gaggtgtacg 16397 gggacgagga catcctcgagcaggcggtcg agcgtctggg cgagtttgcg tacggcaagc 16457 gcagccgccc cgcgcccttgaaagaggagg cggtgtccat cccgctggac cacggcaacc 16517 ccacgccgag cctgaagccggtgaccctgc agcaggtgct accgagcgcg gcgccgcgcc 16577 ggggcttcaa gcgcgagggcggcgaggatc tgtacccgac catgcagctg atggtgccca 16637 agcgccagaa gctggaggacgtgctggagc acatgaaggt ggaccccgag gtgcagcccg 16697 aggtcaaggt gcggcccatcaagcaggtgg ccccgggcct gggcgtgcag accgtggaca 16757 tcaagatccc cacggagcccatggaaacgc agaccgagcc cgtgaagccc agcaccagca 16817 ccatggaggt gcagacggatccctggatgc cagcaccagc ttccaccagc actcgccgaa 16877 gacgcaagta cggcgcggccagcctgctga tgcccaacta cgcgctgcat ccttccatca 16937 tccccacgcc gggctaccgcggcacgcgct tctaccgcgg ctacaccagc agccgccgcc 16997 gcaagaccac cacccgccgccgtcgtcgca gccgccgcag cagcaccgcg acttccgcct 17057 tggtgcggag agtgtatcgcagcgggcgcg agcctctgac cctgccgcgc gcgcgctacc 17117 acccgagcat cgccatttaactaccgcctc ctacttgcag atatggccct cacatgccgc 17177 ctccgcgtcc ccattacgggctaccgagga agaaagccgc gccgtagaag gctgacgggg 17237 aacgggctgc gtcgccatcaccaccggcgg cggcgcgcca tcagcaagcg gttgggggga 17297 ggcttcctgc ccgcgctgatccccatcatc gccgcggcga tcggggcgat ccccggcata 17357 gcttccgtgg cggtgcaggcctctcagcgc cactgagaca caaaaaagca tggatttgta 17417 ataaaaaaaa aaatggactgacgctcctgg tcctgtgatg tgtgttttta gatggaagac 17477 atcaattttt cgtccctggcaccgcgacac ggcacgcggc cgtttatggg cacctggagc 17537 gacatcggca acagccaactgaacgggggc gccttcaatt ggagcagtct ctggagcggg 17597 cttaagaatt tcgggtccacgctcaaaacc tatggcaaca aggcgtggaa cagcagcaca 17657 gggcaggcgc tgagggaaaagctgaaagaa cagaacttcc agcagaaggt ggttgatggc 17717 ctggcctcag gcatcaacggggtggttgac ctggccaacc aggccgtgca gaaacagatc 17777 aacagccgcc tggacgcggtcccgcccgcg gggtccgtgg agatgcccca ggtggaggag 17837 gagctgcctc ccctggacaagcgcggcgac aagcgaccgc gtcccgacgc ggaggagacg 17897 ctgctgacgc acacggacgagccgcccccg tacgaggagg cggtgaaact gggcctgccc 17957 accacgcggc ccgtggcgcctctggccacc ggagtgctga aacccagcag cagccagccc 18017 gcgaccctgg acttgcctccgcctcgcccc tccacagtgg ctaagcccct gccgccggtg 18077 gccgtcgcgt cgcgcgccccccgaggccgc ccccaggcga actggcagag cactctgaac 18137 agcatcgtgg gtctgggagtgcagagtgtg aagcgccgcc gctgctatta aaagacactg 18197 tagcgcttaa cttgcttgtctgtgtgtata tgtatgtccg ccgaccagaa ggaggagtgt 18257 gaagaggcgc gtcgccgagttgcaag atg gcc acc cca tcg atg ctg ccc cag 18310 Met Ala Thr Pro Ser MetLeu Pro Gln 530 535 tgg gcg tac atg cac atc gcc gga cag gac gct tcg gagtac ctg agt 18358 Trp Ala Tyr Met His Ile Ala Gly Gln Asp Ala Ser GluTyr Leu Ser 540 545 550 ccg ggt ctg gtg cag ttc gcc cgc gcc aca gac acctac ttc agt ctg 18406 Pro Gly Leu Val Gln Phe Ala Arg Ala Thr Asp ThrTyr Phe Ser Leu 555 560 565 570 ggg aac aag ttt agg aac ccc acg gtg gcgccc acg cac gat gtg acc 18454 Gly Asn Lys Phe Arg Asn Pro Thr Val AlaPro Thr His Asp Val Thr 575 580 585 acc gac cgc agc cag cgg ctg acg ctgcgc ttc gtg ccc gtg gac cgc 18502 Thr Asp Arg Ser Gln Arg Leu Thr LeuArg Phe Val Pro Val Asp Arg 590 595 600 gag gac aac acc tac tcg tac aaagtg cgc tac acg ctg gcc gtg ggc 18550 Glu Asp Asn Thr Tyr Ser Tyr LysVal Arg Tyr Thr Leu Ala Val Gly 605 610 615 gac aac cgc gtg ctg gac atggcc agc acc tac ttt gac atc cgc ggc 18598 Asp Asn Arg Val Leu Asp MetAla Ser Thr Tyr Phe Asp Ile Arg Gly 620 625 630 gtg ctg gac cgg ggc cctagc ttc aaa ccc tac tct ggc acc gcc tac 18646 Val Leu Asp Arg Gly ProSer Phe Lys Pro Tyr Ser Gly Thr Ala Tyr 635 640 645 650 aac agc cta gctccc aag gga gct ccc aat tcc agc cag tgg gag caa 18694 Asn Ser Leu AlaPro Lys Gly Ala Pro Asn Ser Ser Gln Trp Glu Gln 655 660 665 gca aaa acaggc aat ggg gga act atg gaa aca cac aca tat ggt gtg 18742 Ala Lys ThrGly Asn Gly Gly Thr Met Glu Thr His Thr Tyr Gly Val 670 675 680 gcc ccaatg ggc gga gag aat att aca aaa gat ggt ctt caa att gga 18790 Ala ProMet Gly Gly Glu Asn Ile Thr Lys Asp Gly Leu Gln Ile Gly 685 690 695 actgac gtt aca gcg aat cag aat aaa cca att tat gcc gac aaa aca 18838 ThrAsp Val Thr Ala Asn Gln Asn Lys Pro Ile Tyr Ala Asp Lys Thr 700 705 710ttt caa cca gaa ccg caa gta gga gaa gaa aat tgg caa gaa act gaa 18886Phe Gln Pro Glu Pro Gln Val Gly Glu Glu Asn Trp Gln Glu Thr Glu 715 720725 730 aac ttt tat ggc ggt aga gct ctt aaa aaa gac aca aac atg aaa cct18934 Asn Phe Tyr Gly Gly Arg Ala Leu Lys Lys Asp Thr Asn Met Lys Pro735 740 745 tgc tat ggc tcc tat gct aga ccc acc aat gaa aaa gga ggt caagct 18982 Cys Tyr Gly Ser Tyr Ala Arg Pro Thr Asn Glu Lys Gly Gly GlnAla 750 755 760 aaa ctt aaa gtt gga gat gat gga gtt cca acc aaa gaa ttcgac ata 19030 Lys Leu Lys Val Gly Asp Asp Gly Val Pro Thr Lys Glu PheAsp Ile 765 770 775 gac ctg gct ttc ttt gat act ccc ggt ggc acc gtg aacggt caa gac 19078 Asp Leu Ala Phe Phe Asp Thr Pro Gly Gly Thr Val AsnGly Gln Asp 780 785 790 gag tat aaa gca gac att gtc atg tat acc gaa aacacg tat ttg gaa 19126 Glu Tyr Lys Ala Asp Ile Val Met Tyr Thr Glu AsnThr Tyr Leu Glu 795 800 805 810 act cca gac acg cat gtg gta tac aaa ccaggc aag gat gat gca agt 19174 Thr Pro Asp Thr His Val Val Tyr Lys ProGly Lys Asp Asp Ala Ser 815 820 825 tct gaa att aac ctg gtt cag cag tctatg ccc aac aga ccc aac tac 19222 Ser Glu Ile Asn Leu Val Gln Gln SerMet Pro Asn Arg Pro Asn Tyr 830 835 840 att ggg ttc agg gac aac ttt atcggt ctt atg tac tac aac agc act 19270 Ile Gly Phe Arg Asp Asn Phe IleGly Leu Met Tyr Tyr Asn Ser Thr 845 850 855 ggc aat atg ggt gtg ctt gctggt cag gcc tcc cag ctg aat gct gtg 19318 Gly Asn Met Gly Val Leu AlaGly Gln Ala Ser Gln Leu Asn Ala Val 860 865 870 gtt gat ttg caa gac agaaac acc gag ctg tcc tac cag ctc ttg ctt 19366 Val Asp Leu Gln Asp ArgAsn Thr Glu Leu Ser Tyr Gln Leu Leu Leu 875 880 885 890 gac tct ttg ggtgac aga acc cgg tat ttc agt atg tgg aac cag gcg 19414 Asp Ser Leu GlyAsp Arg Thr Arg Tyr Phe Ser Met Trp Asn Gln Ala 895 900 905 gtg gac agttat gac ccc gat gtg cgc atc atc gaa aac cat ggt gtg 19462 Val Asp SerTyr Asp Pro Asp Val Arg Ile Ile Glu Asn His Gly Val 910 915 920 gag gatgaa ttg cca aac tat tgc ttc ccc ttg gac ggc tct ggc act 19510 Glu AspGlu Leu Pro Asn Tyr Cys Phe Pro Leu Asp Gly Ser Gly Thr 925 930 935 aacgcc gca tac caa ggt gtg aaa gta aaa gat ggt caa gat ggt gat 19558 AsnAla Ala Tyr Gln Gly Val Lys Val Lys Asp Gly Gln Asp Gly Asp 940 945 950gtt gag agt gaa tgg gaa aat gac gat act gtt gca gct cga aat caa 19606Val Glu Ser Glu Trp Glu Asn Asp Asp Thr Val Ala Ala Arg Asn Gln 955 960965 970 tta tgt aaa ggt aac att ttc gcc atg gag att aat ctc cag gct aac19654 Leu Cys Lys Gly Asn Ile Phe Ala Met Glu Ile Asn Leu Gln Ala Asn975 980 985 ctg tgg aga agt ttc ctc tac tcg aac gtg gcc ctg tac ctg cccgac 19702 Leu Trp Arg Ser Phe Leu Tyr Ser Asn Val Ala Leu Tyr Leu ProAsp 990 995 1000 tcc tac aag tac acg ccg acc aac gtc acg ctg ccg acc aacacc 19747 Ser Tyr Lys Tyr Thr Pro Thr Asn Val Thr Leu Pro Thr Asn Thr1005 1010 1015 aac acc tac gat tac atg aat ggc aga gtg aca cct ccc tcgctg 19792 Asn Thr Tyr Asp Tyr Met Asn Gly Arg Val Thr Pro Pro Ser Leu1020 1025 1030 gta gac gcc tac ctc aac atc ggg gcg cgc tgg tcg ctg gacccc 19837 Val Asp Ala Tyr Leu Asn Ile Gly Ala Arg Trp Ser Leu Asp Pro1035 1040 1045 atg gac aac gtc aac ccc ttc aac cac cac cgc aac gcg ggcctg 19882 Met Asp Asn Val Asn Pro Phe Asn His His Arg Asn Ala Gly Leu1050 1055 1060 cgc tac cgc tcc atg ctc ctg ggc aac ggg cgc tac gtg cccttc 19927 Arg Tyr Arg Ser Met Leu Leu Gly Asn Gly Arg Tyr Val Pro Phe1065 1070 1075 cac atc cag gtg ccc caa aag ttt ttc gcc atc aag agc ctcctg 19972 His Ile Gln Val Pro Gln Lys Phe Phe Ala Ile Lys Ser Leu Leu1080 1085 1090 ctc ctg ccc ggg tcc tac acc tac gag tgg aac ttc cgc aaggac 20017 Leu Leu Pro Gly Ser Tyr Thr Tyr Glu Trp Asn Phe Arg Lys Asp1095 1100 1105 gtc aac atg atc ctg cag agc tcc cta ggc aac gac ctg cgcacg 20062 Val Asn Met Ile Leu Gln Ser Ser Leu Gly Asn Asp Leu Arg Thr1110 1115 1120 gac ggg gcc tcc atc gcc ttc acc agc atc aac ctc tac gccacc 20107 Asp Gly Ala Ser Ile Ala Phe Thr Ser Ile Asn Leu Tyr Ala Thr1125 1130 1135 ttc ttc ccc atg gcg cac aac acc gcc tcc acg ctc gag gccatg 20152 Phe Phe Pro Met Ala His Asn Thr Ala Ser Thr Leu Glu Ala Met1140 1145 1150 ctg cgc aac gac acc aac gac cag tcc ttc aac gac tac ctctcg 20197 Leu Arg Asn Asp Thr Asn Asp Gln Ser Phe Asn Asp Tyr Leu Ser1155 1160 1165 gcg gcc aac atg ctc tac ccc atc ccg gcc aac gcc acc aacgtg 20242 Ala Ala Asn Met Leu Tyr Pro Ile Pro Ala Asn Ala Thr Asn Val1170 1175 1180 ccc atc tcc atc ccc tcg cgc aac tgg gcc gcc ttc cgc ggatgg 20287 Pro Ile Ser Ile Pro Ser Arg Asn Trp Ala Ala Phe Arg Gly Trp1185 1190 1195 tcc ttc acg cgc ctg aag acc cgc gag acg ccc tcg ctc ggctcc 20332 Ser Phe Thr Arg Leu Lys Thr Arg Glu Thr Pro Ser Leu Gly Ser1200 1205 1210 ggg ttc gac ccc tac ttc gtc tac tcg ggc tcc atc ccc taccta 20377 Gly Phe Asp Pro Tyr Phe Val Tyr Ser Gly Ser Ile Pro Tyr Leu1215 1220 1225 gac ggc acc ttc tac ctc aac cac acc ttc aag aag gtc tccatc 20422 Asp Gly Thr Phe Tyr Leu Asn His Thr Phe Lys Lys Val Ser Ile1230 1235 1240 acc ttc gac tcc tcc gtc agc tgg ccc ggc aac gac cgc ctcctg 20467 Thr Phe Asp Ser Ser Val Ser Trp Pro Gly Asn Asp Arg Leu Leu1245 1250 1255 acg ccc aac gag ttc gaa atc aag cgc acc gtc gac gga gaggga 20512 Thr Pro Asn Glu Phe Glu Ile Lys Arg Thr Val Asp Gly Glu Gly1260 1265 1270 tac aac gtg gcc cag tgc aac atg acc aag gac tgg ttc ctggtc 20557 Tyr Asn Val Ala Gln Cys Asn Met Thr Lys Asp Trp Phe Leu Val1275 1280 1285 cag atg ctg gcc cac tac aac atc ggc tac cag ggc ttc tacgtg 20602 Gln Met Leu Ala His Tyr Asn Ile Gly Tyr Gln Gly Phe Tyr Val1290 1295 1300 ccc gag ggc tac aag gac cgc atg tac tcc ttc ttc cgc aacttc 20647 Pro Glu Gly Tyr Lys Asp Arg Met Tyr Ser Phe Phe Arg Asn Phe1305 1310 1315 cag ccc atg agc cgc cag gtc gtg gac gag gtc aac tac aaggac 20692 Gln Pro Met Ser Arg Gln Val Val Asp Glu Val Asn Tyr Lys Asp1320 1325 1330 tac cag gcc gtc acc ctg gcc tac cag cac aac aac tcg ggcttc 20737 Tyr Gln Ala Val Thr Leu Ala Tyr Gln His Asn Asn Ser Gly Phe1335 1340 1345 gtc ggc tac ctc gcg ccc acc atg cgc cag ggc cag ccc tacccc 20782 Val Gly Tyr Leu Ala Pro Thr Met Arg Gln Gly Gln Pro Tyr Pro1350 1355 1360 gcc aac tac ccc tac ccg ctc atc ggc aag agc gcc gtc gccagc 20827 Ala Asn Tyr Pro Tyr Pro Leu Ile Gly Lys Ser Ala Val Ala Ser1365 1370 1375 gtc acc cag aaa aag ttc ctc tgc gac cgg gtc atg tgg cgcatc 20872 Val Thr Gln Lys Lys Phe Leu Cys Asp Arg Val Met Trp Arg Ile1380 1385 1390 ccc ttc tcc agc aac ttc atg tcc atg ggc gcg ctc acc gacctc 20917 Pro Phe Ser Ser Asn Phe Met Ser Met Gly Ala Leu Thr Asp Leu1395 1400 1405 ggc cag aac atg ctc tac gcc aac tcc gcc cac gcg cta gacatg 20962 Gly Gln Asn Met Leu Tyr Ala Asn Ser Ala His Ala Leu Asp Met1410 1415 1420 aat ttc gaa gtc gac ccc atg gat gag tcc acc ctt ctc tatgtt 21007 Asn Phe Glu Val Asp Pro Met Asp Glu Ser Thr Leu Leu Tyr Val1425 1430 1435 gtc ttc gaa gtc ttc gac gtc gtc cga gtg cac cag ccc caccgc 21052 Val Phe Glu Val Phe Asp Val Val Arg Val His Gln Pro His Arg1440 1445 1450 ggc gtc atc gaa gcc gtc tac ctg cgc acg ccc ttc tcg gccggc 21097 Gly Val Ile Glu Ala Val Tyr Leu Arg Thr Pro Phe Ser Ala Gly1455 1460 1465 aac gcc acc acc taa gccgctcttg cttcttgcaa gatgacggcgggctccggcg 21152 Asn Ala Thr Thr 1470 agcaggagct cagggccatc ctccgcgacctgggctgcgg gccctgcttc ctgggcacct 21212 tcgacaagcg cttccctgga ttcatggccccgcacaagct ggcctgcgcc atcgtgaaca 21272 cggccggccg cgagaccggg ggcgagcactggctggcctt cgcctggaac ccgcgctccc 21332 acacatgcta cctcttcgac cccttcgggttctcggacga gcgcctcaag cagatctacc 21392 agttcgagta cgagggcctg ctgcgtcgcagcgccctggc caccgaggac cgctgcgtca 21452 ccctggaaaa gtccacccag accgtgcagggtccgcgctc ggccgcctgc gggctcttct 21512 gctgcatgtt cctgcacgcc ttcgtgcactggcccgaccg ccccatggac aagaacccca 21572 ccatgaactt actgacgggg gtgcccaacggcatgctcca gtcgccccag gtggaaccca 21632 ccctgcgccg caaccaggaa gcgctctaccgcttcctcaa tgcccactcc gcctactttc 21692 gctcccaccg cgcgcgcatc gagaaggccaccgccttcga ccgcatgaat caagacatgt 21752 aaaaaaccgg tgtgtgtatg tgaatgctttattcataata aacagcacat gtttatgcca 21812 ccttctctga ggctctgact ttatttagaaatcgaagggg ttctgccggc tctcggcatg 21872 gcccgcgggc agggatacgt tgcggaactggtacttgggc agccacttga actcggggat 21932 cagcagcttg ggcacgggga ggtcggggaacgagtcgctc cacagcttgc gcgtgagttg 21992 cagggcgccc agcaggtcgg gcgcggagatcttgaaatcg cagttgggac ccgcgttctg 22052 cgcgcgagag ttgcggtaca cggggttgcagcactggaac accatcaggg ccgggtgctt 22112 cacgcttgcc agcaccgtcg cgtcggtgatgccctccacg tccagatcct cggcgttggc 22172 catcccgaag ggggtcatct tgcaggtctgccgccccatg ctgggcacgc agccgggctt 22232 gtggttgcaa tcgcagtgca gggggatcagcatcatctgg gcctgctcgg agctcatgcc 22292 cgggtacatg gccttcatga aagcctccagctggcggaag gcctgctgcg ccttgccgcc 22352 ctcggtgaag aagaccccgc aggacttgctagagaactgg ttggtggcgc agccggcgtc 22412 gtgcacgcag cagcgcgcgt cgttgttggccagctgcacc acgctgcgcc cccagcggtt 22472 ctgggtgatc ttggcccggt tggggttctccttcagcgcg cgctgcccgt tctcgctcgc 22532 cacatccatc tcgatagtgt gctccttctggatcatcacg gtcccgtgca ggcaccgcag 22592 cttgccctcg gcttcggtgc agccgtgcagccacagcgcg cagccggtgc actcccagtt 22652 cttgtgggcg atctgggagt gcgagtgcacgaagccctgc aggaagcggc ccatcatcgc 22712 ggtcagggtc ttgttgctgg tgaaggtcagcgggatgccg cggtgctcct cgttcacata 22772 caggtggcag atgcggcggt acacctcgccctgctcgggc atcagctgga aggcggactt 22832 caggtcgctc tccacgcggt accggtccatcagcagcgtc atcacttcca tgcccttctc 22892 ccaggccgaa acgatcggca ggctcagggggttcttcacc gccattgtca tcttagtcgc 22952 cgccgccgag gtcagggggt cgttctcgtccagggtctca aacactcgct tgccgtcctt 23012 ctcgatgatg cgcacggggg gaaagctgaagcccacggcc gccagctcct cctcggcctg 23072 cctttcgtcc tcgctgtcct ggctgatgtcttgcaaaggc acatgcttgg tcttgcgggg 23132 tttctttttg ggcggcagag gcggcggcgatgtgctggga gagcgcgagt tctcgttcac 23192 cacgactatt tcttcttctt ggccgtcgtccgagaccacg cggcggtagg catgcctctt 23252 ctggggcaga ggcggaggcg acgggctctcgcggttcggc gggcggctgg cagagcccct 23312 tccgcgttcg ggggtgcgct cctggcggcgctgctctgac tgacttcctc cgcggccggc 23372 cattgtgttc tcctagggag caacaacaagcatggagact cagccatcgt cgccaacatc 23432 gccatctgcc cccgccgcca ccgccgacgagaaccagcag cagaatgaaa gcttaaccgc 23492 cccgccgccc agccccacct ccgacgccgcggccccagac atgcaagaga tggaggaatc 23552 catcgagatt gacctgggct acgtgacgcccgcggagcac gaggaggagc tggcagcgcg 23612 cttttcagcc ccggaagaga accaccaagagcagccagag caggaagcag agaacgagca 23672 gaaccaggct gggcacgagc atggcgactacctgagcggg gcagaggacg tgctcatcaa 23732 gcatctggcc cgccaatgca tcatcgtcaaggacgcgctg ctcgaccgcg ccgaggtgcc 23792 cctcagcgtg gcggagctca gccgcgcctacgagcgcaac ctcttctcgc cgcgcgtgcc 23852 ccccaagcgc cagcccaacg gcacctgtgagcccaacccg cgcctcaact tctacccggt 23912 cttcgcggtg cccgaggccc tggccacctaccacctcttt ttcaagaacc aaaggatccc 23972 cgtctcctgc cgcgccaacc gcacccgcgccgacgccctg ctcaacctgg gccccggcgc 24032 ccgcctacct gatatcacct ccttggaagaggttcccaag atcttcgagg gtctgggcag 24092 cgacgagact cgggccgcga acgctctgcaaggaagcgga gaggagcatg agcaccacag 24152 cgccctggtg gagttggaag gcgacaacgcgcgcctggcg gtcctcaagc gcacggtcga 24212 gctgacccac ttcgcctacc cggcgctcaacctgcccccc aaggtcatga gcgccgtcat 24272 ggaccaggtg ctcatcaagc gcgcctcgcccctctcggag gaggagatgc aggaccccga 24332 gagttcggac gagggcaagc ccgtggtcagcgacgagcag ctggcgcgct ggctgggagc 24392 gagtagcacc ccccagagcc tggaagagcggcgcaagctc atgatggccg tggtcctggt 24452 gaccgtggag ctggagtgtc tgcgccgcttctttgccgac gcggagaccc tgcgcaaggt 24512 cgaggagaac ctgcactacc tcttcaggcacgggttcgtg cgccaggcct gcaagatctc 24572 caacgtggag ctgaccaacc tggtctcctacatgggcatc ctgcacgaga accgcctggg 24632 gcaaaacgtg ctgcacacca ccctgcgcggggaggcccgc cgcgactaca tccgcgactg 24692 cgtctacctg tacctctgcc acacctggcagacgggcatg ggcgtgtggc agcagtgcct 24752 ggaggagcag aacctgaaag agctctgcaagctcctgcag aagaacctca aggccctgtg 24812 gaccgggttc gacgagcgta ccaccgcctcggacctggcc gacctcatct tccccgagcg 24872 cctgcggctg acgctgcgca acgggctgcccgactttatg agccaaagca tgttgcaaaa 24932 ctttcgctct ttcatcctcg aacgctccgggatcctgccc gccacctgct ccgcgctgcc 24992 ctcggacttc gtgccgctga ccttccgcgagtgccccccg ccgctctgga gccactgcta 25052 cttgctgcgc ctggccaact acctggcctaccactcggac gtgatcgagg acgtcagcgg 25112 cgagggtctg ctggagtgcc actgccgctgcaacctctgc acgccgcacc gctccctggc 25172 ctgcaacccc cagctgctga gcgagacccagatcatcggc accttcgagt tgcaaggccc 25232 cggcgacggc gagggcaagg ggggtctgaaactcaccccg gggctgtgga cctcggccta 25292 cttgcgcaag ttcgtgcccg aggactaccatcccttcgag atcaggttct acgaggacca 25352 atcccagccg cccaaggccg agctgtcggcctgcgtcatc acccaggggg ccatcctggc 25412 ccaattgcaa gccatccaga aatcccgccaagaatttctg ctgaaaaagg gccacggggt 25472 ctacttggac ccccagaccg gagaggagctcaaccccagc ttcccccagg atgccccgag 25532 gaagcagcaa gaagctgaaa gtggagctgccgccgccgga ggatttggag gaagactggg 25592 agagcagtca ggcagaggag gaggagatggaagactggga cagcactcag gcagaggagg 25652 acagcctgca agacagtctg gaggaggaagacgaggtgga ggaggcagag gaagaagcag 25712 ccgccgccag accgtcgtcc tcggcggagaaagcaagcag cacggatacc atctccgctc 25772 cgggtcgggg tcgcggcggc cgggcccacagtaggtggga cgagaccggg cgcttcccga 25832 accccaccac ccagaccggt aagaaggagcggcagggata caagtcctgg cgggggcaca 25892 aaaacgccat cgtctcctgc ttgcaagcctgcgggggcaa catctccttc acccggcgct 25952 acctgctctt ccaccgcggg gtgaacttcccccgcaacat cttgcattac taccgtcacc 26012 tccacagccc ctactactgt ttccaagaagaggcagaaac ccagcagcag cagaaaacca 26072 gcggcagcag cagctagaaa atccacagcggcggcaggtg gactgaggat cgcggcgaac 26132 gagccggcgc agacccggga gctgaggaaccggatctttc ccaccctcta tgccatcttc 26192 cagcagagtc gggggcagga gcaggaactgaaagtcaaga accgttctct gcgctcgctc 26252 acccgcagtt gtctgtatca caagagcgaagaccaacttc agcgcactct cgaggacgcc 26312 gaggctctct tcaacaagta ctgcgcgctcactcttaaag agtagcccgc gcccgcccac 26372 acacggaaaa aggcgggaat tacgtcaccacctgcgccct tcgcccgacc atcatgagca 26432 aagagattcc cacgccttac atgtggagctaccagcccca gatgggcctg gccgccggcg 26492 ccgcccagga ctactccacc cgcatgaactggctcagtgc cgggcccgcg atgatctcac 26552 gggtgaatga catccgcgcc caccgaaaccagatactcct agaacagtca gcgatcaccg 26612 ccacgccccg ccatcacctt aatccgcgtaattggcccgc cgccctggtg taccaggaaa 26672 ttccccagcc cacgaccgta ctacttccgcgagacgccca ggccgaagtc cagctgacta 26732 actcaggtgt ccagctggcc ggcggcgccgccctgtgtcg tcaccgcccc gctcagggta 26792 taaagcggct ggtgatccga ggcagaggcacacagctcaa cgacgaggtg gtgagctctt 26852 cgctgggtct gcgacctgac ggagtcttccaactcgccgg atcggggaga tcttccttca 26912 cgcctcgtca ggccgtcctg actttggagagttcgtcctc gcagccccgc tcgggcggca 26972 tcggcactct ccagttcgtg gaggagttcactccctcggt ctacttcaac cccttctccg 27032 gctcccccgg ccactacccg gacgagttcatcccgaactt cgacgccatc agcgagtcgg 27092 tggacggcta cgattgaatg tcccatggtggcgcagctga cctagctcgg cttcgacacc 27152 tggaccactg ccgccgcttc cgctgcttcgctcgggatct cgccgagttt gcctactttg 27212 agctgcccga ggagcaccct cagggcccagcccacggagt gcggatcatc gtcgaagggg 27272 gcctcgactc ccacctgctt cggatcttcagccagcgacc gatcctggtc gagcgcgaac 27332 aaggacagac ccttcttact ttgtactgcatctgcaacca ccccggcctg catgaaagtc 27392 tttgttgtct gctgtgtact gagtataataaaagctgaga tcagcgacta ctccggactc 27452 gattgtggtg ttcctgctat caaccggtccctgttcttca ccgggaacga gaccgagctc 27512 cagctccagt gtaagcccca caagaagtacctcacctggc tgttccaggg ctccccgatc 27572 gccgttgtca accactgcga caacgacggagtcctgctga gcggccctgc caaccttact 27632 ttttccaccc gcagaagcaa gctccagctcttccaaccct tcctccccgg gacctatcag 27692 tgcgtctcag gaccctgcca tcacaccttccacctgatcc cgaataccac agcgccgctc 27752 cccgctacta acaaccaaac tacccaccaacgccaccgtc gcgacctttc ctctgaatct 27812 aataccacta ccggaggtga gctccgaggtcgaccaacct ctgggattta ctacggcccc 27872 tgggaggtgg tggggttaat agcgctaggcctagttgcgg gtgggctttt ggttctctgc 27932 tacctatacc tcccttgctg ttcgtacttagtggtgctgt gttgctggtt taagaaatgg 27992 ggaagatcac cctagtgagc tgcggtgcgctggtggcggt gttgctttcg attgtgggac 28052 tgggcggcgc ggctgtagtg aaggagaaggccgatccctg cttgcatttc aatcccaaca 28112 aatgccagct gagttttcag cccgatggcaatcggtgcgc ggtactgatc aagtgcggat 28172 gggaatgcga gaacgtgaga atcgagtacaataacaagac tcggaacaat actctcgcgt 28232 ccgtgtggca gcccggggac cccgagtggtacaccgtctc tgtccccggt gctgacggct 28292 ccccgcgcac cgtgaataat actttcatttttgcgcacat gtgcaacacg gtcatgtgga 28352 tgagcaagca gtacgatatg tggccccccacgaaggagaa catcgtggtc ttctccatcg 28412 cttacagcct gtgcacggcg ctaatcaccgctatcgtgtg cctgagcatt cacatgctca 28472 tcgctattcg ccccagaaat aatgccgagaaagagaaaca gccataacac gttttttcac 28532 acaccttgtt tttacagaca atgcgtctgttaaatttttt aaacattgtg ctcagtattg 28592 cttatgcctc tggttatgca aacatacagaaaacccttta tgtaggatct gatggtacac 28652 tagagggtac ccaatcacaa gccaaggttgcatggtattt ttatagaacc aacactgatc 28712 cagttaaact ttgtaagggt gaattgccgcgtacacataa aactccactt acatttagtt 28772 gcagcaataa taatcttaca cttttttcaattacaaaaca atatactggt acttattaca 28832 gtacaaactt tcatacagga caagataaatattatactgt taaggtagaa aatcctacca 28892 ctcctagaac taccaccacc accactactgcaaagcccac tgtgaaaact acaactagga 28952 ccaccacaac tacagaaacc accaccagcacaacacttgc tgcaactaca cacacacaca 29012 ctaagctaac cttacagacc actaatgatttgatcgccct gctgcaaaag ggggataaca 29072 gcaccacttc caatgaggag atacccaaatccatgattgg cattattgtt gctgtagtgg 29132 tgtgcatgtt gatcatcgcc ttgtgcatggtgtactatgc cttctgctac agaaagcaca 29192 gactgaacga caagctggaa cacttactaagtgttgaatt ttaatttttt agaaccatga 29252 agatcctagg cctttttagt ttttctatcattacctctgc tctttgtgaa tcagtggata 29312 gagatgttac tattaccact ggttctaattatacactgaa agggccaccc tcaggtatgc 29372 tttcgtggta ttgctatttt ggaactgacactgatcaaac tgaattatgc aattttcaaa 29432 aaggcaaaac ctcaaactct aaaatctctaattatcaatg caatggcact gatctgatac 29492 tactcaatgt cacgaaagca tatggtggcagttattattg ccctggacaa aacactgaag 29552 aaatgatttt ttacaaagtg gaagtggttgatcccactac accacccacc accacaacta 29612 ttcataccac acacacagaa caaacaccagaggcaacaga agcagagttg gccttccagg 29672 ttcacggaga ttcctttgct gtcaatacccctacacccga tcagcggtgt ccggggccgc 29732 tagtcagcgg cattgtcggt gtgctttcgggattagcagt cataatcatc tgcatgttca 29792 tttttgcttg ctgctataga aggctttaccgacaaaaatc agacccactg ctgaacctct 29852 atgtttaatt ttttccagag ccatgaaggcagttagcgct ctagtttttt gttctttgat 29912 tggcattgtt tttaatagta aaattaccagagttagcttt attaaacatg ttaatgtaac 29972 tgaaggagat aacatcacac tagcaggtgtagaaggtgct caaaacacca cctggacaaa 30032 ataccatcta ggatggagag atatttgcacctggaatgta acttattatt gcataggagt 30092 taatcttacc attgttaacg ctaaccaatctcagaatggg ttaattaaag gacagagtgt 30152 tagtgtgacc agtgatgggt actatacccagcatagtttt aactacaaca ttactgtcat 30212 accactgcct acgcctagcc cacctagcactaccacacag acaaccacat acagtacatc 30272 aaatcagcct accaccacta cagcagcagaggttgccagc tcgtctgggg tccgagtggc 30332 atttttgatg ttggccccat ctagcagtcccactgctagt accaatgagc agactactga 30392 atttttgtcc actgtcgaga gccacaccacagctacctcc agtgccttct ctagcaccgc 30452 caatctctcc tcgctttcct ctacaccaatcagccccgct actactccta gccccgctcc 30512 tcttcccact cccctgaagc aaacagacggcggcatgcaa tggcagatca ccctgctcat 30572 tgtgatcggg ttggtcatcc tggccgtgttgctctactac atcttctgcc gccgcattcc 30632 caacgcgcac cgcaagccgg cctacaagcccatcgttatc gggcagccgg agccgcttca 30692 ggtggaaggg ggtctaagga atcttctcttctcttttaca gtatggtgat tgaactatga 30752 ttcctagaca attcttgatc actattcttatctgcctcct ccaagtctgt gccaccctcg 30812 ctctggtggc caacgccagt ccagactgtattgggccctt cgcctcctac gtgctctttg 30872 ccttcgtcac ctgcatctgc tgctgtagcatagtctgcct gcttatcacc ttcttccagt 30932 tcattgactg gatctttgtg cgcatcgcctacctgcgcca ccacccccag taccgcgacc 30992 agcgagtggc gcagctgctc aggctcctctgataagcatg cgggctctgc tacttctcgc 31052 gcttctgctg ttagtgctcc cccgtcccgtcgacccccgg tcccccactc agtcccccga 31112 ggaggttcgc aaatgcaaat tccaagaaccctggaaattc ctcaaatgct accgccaaaa 31172 atcagacatg catcccagct ggatcatgatcattgggatc gtgaacattc tggcctgcac 31232 cctcatctcc tttgtgattt acccctgctttgactttggt tggaactcgc cagaggcgct 31292 ctatctcccg cctgaacctg acacaccaccacagcagcaa cctcaggcac acgcactacc 31352 accaccacag cctaggccac aatacatgcccatattagac tatgaggccg agccacagcg 31412 acccatgctc cccgctatta gttacttcaatctaaccggc ggagatgact gacccactgg 31472 ccaataacaa cgtcaacgac cttctcctggacatggacgg ccgcgcctcg gagcagcgac 31532 tcgcccaact tcgcattcgt cagcagcaggagagagccgt caaggagctg caggacggca 31592 tagccatcca ccagtgcaag agaggcatcttctgcctggt gaaacaggcc aagatctcct 31652 acgaggtcac ccagaccgac catcgcctctcctacgagct cctgcagcag cgccagaagt 31712 tcacctgcct ggtcggagtc aaccccatcgtcatcaccca gcagtcgggc gataccaagg 31772 ggtgcatcca ctgctcctgc gactcccccgactgcgtcca cactctgatc aagaccctct 31832 gcggcctccg cgacctcctc cccatgaactaatcaccccc ttatccagtg aaataaagat 31892 catattgatg atgatttaaa taaaaaaaataatcatttga tttgaaataa agatacaatc 31952 atattgatga tttgagttta acaaaaataaagaatcactt acttgaaatc tgataccagg 32012 tctctgtcca tgttttctgc caacaccacctcactcccct cttcccagct ctggtactgc 32072 aggccccggc gggctgcaaa cttcctccacacgctgaagg ggatgtcaaa ttcctcctgt 32132 ccctcaatct tcattttatc ttctatcagatg tcc aaa aag cgc gtc cgg gtg 32185 Met Ser Lys Lys Arg Val Arg Val1475 gat gat gac ttc gac ccc gtc tac ccc tac gat gca gac aac gca 32230Asp Asp Asp Phe Asp Pro Val Tyr Pro Tyr Asp Ala Asp Asn Ala 1480 14851490 ccg acc gtg ccc ttc atc aac ccc ccc ttc gtc tct tca gat gga 32275Pro Thr Val Pro Phe Ile Asn Pro Pro Phe Val Ser Ser Asp Gly 1495 15001505 ttc caa gag aag ccc ctg ggg gtg ttg tcc ctg cga ctg gct gac 32320Phe Gln Glu Lys Pro Leu Gly Val Leu Ser Leu Arg Leu Ala Asp 1510 15151520 ccc gtc acc acc aag aac ggg gaa atc acc ctc aag ctg gga gag 32365Pro Val Thr Thr Lys Asn Gly Glu Ile Thr Leu Lys Leu Gly Glu 1525 15301535 ggg gtg gac ctc gac tcg tcg gga aaa ctc atc tcc aac acg gcc 32410Gly Val Asp Leu Asp Ser Ser Gly Lys Leu Ile Ser Asn Thr Ala 1540 15451550 acc aag gcc gcc gcc cct ctc agt att tca aac aac acc att tcc 32455Thr Lys Ala Ala Ala Pro Leu Ser Ile Ser Asn Asn Thr Ile Ser 1555 15601565 ctt aaa act gct gcc cct ttc tac aac aac aat gga act tta agc 32500Leu Lys Thr Ala Ala Pro Phe Tyr Asn Asn Asn Gly Thr Leu Ser 1570 15751580 ctc aat gtc tcc aca cca tta gca gta ttt ccc aca ttt aac act 32545Leu Asn Val Ser Thr Pro Leu Ala Val Phe Pro Thr Phe Asn Thr 1585 15901595 tta ggc ata agt ctt gga aac ggt ctt cag act tca aat aag ttg 32590Leu Gly Ile Ser Leu Gly Asn Gly Leu Gln Thr Ser Asn Lys Leu 1600 16051610 ttg act gta caa cta act cat cct ctt aca ttc agc tca aat agc 32635Leu Thr Val Gln Leu Thr His Pro Leu Thr Phe Ser Ser Asn Ser 1615 16201625 atc aca gta aaa aca gac aaa ggg cta tat att aac tcc agt gga 32680Ile Thr Val Lys Thr Asp Lys Gly Leu Tyr Ile Asn Ser Ser Gly 1630 16351640 aac aga gga ctt gag gct aat ata agc cta aaa aga gga cta gtt 32725Asn Arg Gly Leu Glu Ala Asn Ile Ser Leu Lys Arg Gly Leu Val 1645 16501655 ttt gac ggt aat gct att gca aca tat att gga aat ggc tta gac 32770Phe Asp Gly Asn Ala Ile Ala Thr Tyr Ile Gly Asn Gly Leu Asp 1660 16651670 tat gga tct tat gat agt gat gga aaa aca aga ccc gta att acc 32815Tyr Gly Ser Tyr Asp Ser Asp Gly Lys Thr Arg Pro Val Ile Thr 1675 16801685 aaa att gga gca gga tta aat ttt gat gct aac aaa gca ata gct 32860Lys Ile Gly Ala Gly Leu Asn Phe Asp Ala Asn Lys Ala Ile Ala 1690 16951700 gtc aaa cta ggc aca ggt tta agt ttt gac tcc gct ggt gcc ttg 32905Val Lys Leu Gly Thr Gly Leu Ser Phe Asp Ser Ala Gly Ala Leu 1705 17101715 aca gct gga aac aaa cag gat gac aag cta aca ctt tgg act acc 32950Thr Ala Gly Asn Lys Gln Asp Asp Lys Leu Thr Leu Trp Thr Thr 1720 17251730 cct gac cca agc cct aat tgt caa tta ctt tca gac aga gat gcc 32995Pro Asp Pro Ser Pro Asn Cys Gln Leu Leu Ser Asp Arg Asp Ala 1735 17401745 aaa ttt act ctc tgt ctt aca aaa tgc ggt agt caa ata cta ggc 33040Lys Phe Thr Leu Cys Leu Thr Lys Cys Gly Ser Gln Ile Leu Gly 1750 17551760 act gtg gca gtg gcg gct gtt act gta gga tca gca cta aat cca 33085Thr Val Ala Val Ala Ala Val Thr Val Gly Ser Ala Leu Asn Pro 1765 17701775 att aat gac aca gtc aaa agc gcc ata gtt ttc ctt aga ttt gat 33130Ile Asn Asp Thr Val Lys Ser Ala Ile Val Phe Leu Arg Phe Asp 1780 17851790 tcc gat ggt gta ctc atg tca aac tca tca atg gta ggt gat tac 33175Ser Asp Gly Val Leu Met Ser Asn Ser Ser Met Val Gly Asp Tyr 1795 18001805 tgg aac ttt agg gag gga cag acc act caa agt gta gcc tat aca 33220Trp Asn Phe Arg Glu Gly Gln Thr Thr Gln Ser Val Ala Tyr Thr 1810 18151820 aat gct gtg gga ttc atg cca aat ata ggt gca tat cca aaa acc 33265Asn Ala Val Gly Phe Met Pro Asn Ile Gly Ala Tyr Pro Lys Thr 1825 18301835 caa agt aaa aca cct aaa aat agc ata gtc agt cag gta tat tta 33310Gln Ser Lys Thr Pro Lys Asn Ser Ile Val Ser Gln Val Tyr Leu 1840 18451850 act gga gaa act act atg cca atg aca cta acc ata act ttc aat 33355Thr Gly Glu Thr Thr Met Pro Met Thr Leu Thr Ile Thr Phe Asn 1855 18601865 ggc act gat gaa aaa gac aca acc cca gtt agc acc tac tct atg 33400Gly Thr Asp Glu Lys Asp Thr Thr Pro Val Ser Thr Tyr Ser Met 1870 18751880 act ttt aca tgg cag tgg act gga gac tat aag gac aaa aat att 33445Thr Phe Thr Trp Gln Trp Thr Gly Asp Tyr Lys Asp Lys Asn Ile 1885 18901895 acc ttt gct acc aac tca ttc tct ttt tcc tac atc gcc cag gaa 33490Thr Phe Ala Thr Asn Ser Phe Ser Phe Ser Tyr Ile Ala Gln Glu 1900 19051910 taa tcccacccag caagccaacc ccttttccca ccacctttgt ctatatggaa 33543actctgaaac agaaaaataa agttcaagtg ttttattgaa tcaacagttt tacaggactc 33603gagcagttat ttttcctcca ccctcccagg acatggaata caccaccctc tccccccgca 33663cagccttgaa catctgaatg ccattggtga tggacatgct tttggtctcc acgttccaca 33723cagtttcaga gcgagccagt ctcggatcgg tcagggagat gaaaccctcc gggcactccc 33783gcatctgcac ctcacagctc aacagctgag gattgtcctc ggtggtcggg atcacggtta 33843tctggaagaa gcagaagagc ggcggtggga atcatagtcc gcgaacggga tcggccggtg 33903gtgtcgcatc aggccccgca gcagtcgctg ccgccgccgc tccgtcaagc tgctgctcag 33963ggggttcggg tccagggact ccctcagcat gatgcccacg gccctcagca tcagtcgtct 34023ggtgcggcgg gcgcagcagc gcatgcgaat ctcgctcagg tcactgcagt acgtgcaaca 34083caggaccacc aggttgttca acagtccata gttcaacacg ctccagccga aactcatcgc 34143gggaaggatg ctacccacgt ggccgtcgta ccagatcctc aggtaaatca agtggcgctc 34203cctccagaag acgctgccca tgtacatgat ctccttgggc atgtggcggt tcaccacctc 34263ccggtaccac atcaccctct ggttgaacat gcagccccgg atgatcctgc ggaaccacag 34323ggccagcacc gccccgcccg ccatgcagcg aagagacccc ggatcccggc aatgacaatg 34383gaggacccac cgctcgtacc cgtggatcat ctgggagctg aacaagtcta tgttggcaca 34443gcacaggcat atgctcatgc atctcttcag cactctcagc tcctcggggg tcaaaaccat 34503atcccagggc acggggaact cttgcaggac agcgaacccc gcagaacagg gcaatcctcg 34563cacataactt acattgtgca tggacagggt atcgcaatca ggcagcaccg ggtgatcctc 34623caccagagaa gcgcgggtct cggtctcctc acagcgtggt aagggggccg gccgatacgg 34683gtgatggcgg gacgcggctg atcgtgttct cgaccgtgtc atgatgcagt tgctttcgga 34743cattttcgta cttgctgtag cagaacctgg tccgggcgct gcacaccgat cgccggcggc 34803ggtctcggcg cttggaacgc tcggtgttaa agttgtaaaa cagccactct ctcagaccgt 34863gcagcagatc tagggcctca ggagtgatga agatcccatc atgcctgata gctctgatca 34923catcgaccac cgtggaatgg gccaggccca gccagatgat gcaattttgt tgggtttcgg 34983tgacggcggg ggagggaaga acaggaagaa ccatgattaa cttttaatcc aaacggtctc 35043ggagcacttc aaaatgaagg tcacggagat ggcacctctc gcccccgctg tgttggtgga 35103aaataacagc caggtcaaag gtgatacggt tctcgagatg ttccacggtg gcttccagca 35163aagcctccac gcgcacatcc agaaacaaga caatagcgaa agcgggaggg ttctctaatt 35223cctcaaccat catgttacac tcctgcacca tccccagata attttcattt ttccagcctt 35283gaatgattcg aactagttcc tgaggtaaat ccaagccagc catgataaaa agctcgcgca 35343gagcaccctc caccggcatt cttaagcaca ccctcataat tccaagatat tctgctcctg 35403gttcacctgc agcagattga caagcggaat atcaaaatct ctgccgcgat ccctgagctc 35463ctccctcagc aataactgta agtactcttt catatcgtct ccgaaatttt tagccatagg 35523acccccagga ataagagaag ggcaagccac attacagata aaccgaagtc ccccccagtg 35583agcattgcca aatgtaagat tgaaataagc atgctggcta gacccggtga tatcttccag 35643ataactggac agaaaatcgg gtaagcaatt tttaagaaaa tcaacaaaag aaaaatcttc 35703caggtgcacg tttagggcct cgggaacaac gatggagtaa gtgcaagggg tgcgttccag 35763catggttagt tagctgatct gtaaaaaaac aaaaaataaa acattaaacc atgctagcct 35823ggcgaacagg tgggtaaatc gttctctcca gcaccaggca ggccacgggg tctccggcgc 35883gaccctcgta aaaattgtcg ctatgattga aaaccatcac agagagacgt tcccggtggc 35943cggcgtgaat gattcgagaa gaagcataca cccccggaac attggagtcc gtgagtgaaa 36003aaaagcggcc gaggaagcaa tgaggcacta caacgctcac tctcaagtcc agcaaagcga 36063tgccatgcgg atgaagcaca aaattttcag gtgcgtaaaa aatgtaatta ctcccctcct 36123gcacaggcag cgaagctccc gatccctcca gatacacata caaagcctca gcgtccatag 36183cttaccgagc ggcagcagca gcggcacaca acaggcgcaa gagtcagaga aaagactgag 36243ctctaacctg tccgcccgct ctctgctcaa tatatagccc cagatctaca ctgacgtaaa 36303ggccaaagtc taaaaatacc cgccaaataa tcacacacgc ccagcacacg cccagaaacc 36363ggtgacacac tcagaaaaat acgcgcactt cctcaaacgg ccaaactgcc gtcatttccg 36423ggttcccacg ctacgtcatc aaaacacgac tttcaaattc cgtcgaccgt taaaaacatc 36483acccgccccg cccctaacgg tcgccgctcc cgcagccaat caccttcctc cctccccaaa 36543ttcaaacagc tcatttgcat attaacgcgc accaaaagtt tgaggtatat tattgatgat 36603g 36604 6 529 PRT chimpanzee adenovirus serotype Pan6 6 Met Met Arg ArgVal Tyr Pro Glu Gly Pro Pro Pro Ser Tyr Glu Ser 1 5 10 15 Val Met GlnGln Ala Val Ala Ala Ala Met Gln Pro Pro Leu Glu Ala 20 25 30 Pro Tyr ValPro Pro Arg Tyr Leu Ala Pro Thr Glu Gly Arg Asn Ser 35 40 45 Ile Arg TyrSer Glu Leu Ala Pro Leu Tyr Asp Thr Thr Arg Leu Tyr 50 55 60 Leu Val AspAsn Lys Ser Ala Asp Ile Ala Ser Leu Asn Tyr Gln Asn 65 70 75 80 Asp HisSer Asn Phe Leu Thr Thr Val Val Gln Asn Asn Asp Phe Thr 85 90 95 Pro ThrGlu Ala Ser Thr Gln Thr Ile Asn Phe Asp Glu Arg Ser Arg 100 105 110 TrpGly Gly Gln Leu Lys Thr Ile Met His Thr Asn Met Pro Asn Val 115 120 125Asn Glu Phe Met Tyr Ser Asn Lys Phe Lys Ala Arg Val Met Val Ser 130 135140 Arg Lys Thr Pro Asn Gly Val Asp Asp Asp Tyr Asp Gly Ser Gln Asp 145150 155 160 Glu Leu Thr Tyr Glu Trp Val Glu Phe Glu Leu Pro Glu Gly AsnPhe 165 170 175 Ser Val Thr Met Thr Ile Asp Leu Met Asn Asn Ala Ile IleAsp Asn 180 185 190 Tyr Leu Ala Val Gly Arg Gln Asn Gly Val Leu Glu SerAsp Ile Gly 195 200 205 Val Lys Phe Asp Thr Arg Asn Phe Arg Leu Gly TrpAsp Pro Val Thr 210 215 220 Glu Leu Val Met Pro Gly Val Tyr Thr Asn GluAla Phe His Pro Asp 225 230 235 240 Ile Val Leu Leu Pro Gly Cys Gly ValAsp Phe Thr Glu Ser Arg Leu 245 250 255 Ser Asn Leu Leu Gly Ile Arg LysArg Gln Pro Phe Gln Glu Gly Phe 260 265 270 Gln Ile Leu Tyr Glu Asp LeuGlu Gly Gly Asn Ile Pro Ala Leu Leu 275 280 285 Asp Val Glu Ala Tyr GluLys Ser Lys Glu Asp Ser Thr Ala Ala Ala 290 295 300 Thr Ala Ala Val AlaThr Ala Ser Thr Glu Val Arg Gly Asp Asn Phe 305 310 315 320 Ala Ser AlaAla Ala Ala Ala Glu Ala Ala Glu Thr Glu Ser Lys Ile 325 330 335 Val IleGln Pro Val Glu Lys Asp Ser Lys Asp Arg Ser Tyr Asn Val 340 345 350 LeuAla Asp Lys Lys Asn Thr Ala Tyr Arg Ser Trp Tyr Leu Ala Tyr 355 360 365Asn Tyr Gly Asp Pro Glu Lys Gly Val Arg Ser Trp Thr Leu Leu Thr 370 375380 Thr Ser Asp Val Thr Cys Gly Val Glu Gln Val Tyr Trp Ser Leu Pro 385390 395 400 Asp Met Met Gln Asp Pro Val Thr Phe Arg Ser Thr Arg Gln ValSer 405 410 415 Asn Tyr Pro Val Val Gly Ala Glu Leu Leu Pro Val Tyr SerLys Ser 420 425 430 Phe Phe Asn Glu Gln Ala Val Tyr Ser Gln Gln Leu ArgAla Phe Thr 435 440 445 Ser Leu Thr His Val Phe Asn Arg Phe Pro Glu AsnGln Ile Leu Val 450 455 460 Arg Pro Pro Ala Pro Thr Ile Thr Thr Val SerGlu Asn Val Pro Ala 465 470 475 480 Leu Thr Asp His Gly Thr Leu Pro LeuArg Ser Ser Ile Arg Gly Val 485 490 495 Gln Arg Val Thr Val Thr Asp AlaArg Arg Arg Thr Cys Pro Tyr Val 500 505 510 Tyr Lys Ala Leu Gly Val ValAla Pro Arg Val Leu Ser Ser Arg Thr 515 520 525 Phe 7 942 PRT chimpanzeeadenovirus serotype Pan6 7 Met Ala Thr Pro Ser Met Leu Pro Gln Trp AlaTyr Met His Ile Ala 1 5 10 15 Gly Gln Asp Ala Ser Glu Tyr Leu Ser ProGly Leu Val Gln Phe Ala 20 25 30 Arg Ala Thr Asp Thr Tyr Phe Ser Leu GlyAsn Lys Phe Arg Asn Pro 35 40 45 Thr Val Ala Pro Thr His Asp Val Thr ThrAsp Arg Ser Gln Arg Leu 50 55 60 Thr Leu Arg Phe Val Pro Val Asp Arg GluAsp Asn Thr Tyr Ser Tyr 65 70 75 80 Lys Val Arg Tyr Thr Leu Ala Val GlyAsp Asn Arg Val Leu Asp Met 85 90 95 Ala Ser Thr Tyr Phe Asp Ile Arg GlyVal Leu Asp Arg Gly Pro Ser 100 105 110 Phe Lys Pro Tyr Ser Gly Thr AlaTyr Asn Ser Leu Ala Pro Lys Gly 115 120 125 Ala Pro Asn Ser Ser Gln TrpGlu Gln Ala Lys Thr Gly Asn Gly Gly 130 135 140 Thr Met Glu Thr His ThrTyr Gly Val Ala Pro Met Gly Gly Glu Asn 145 150 155 160 Ile Thr Lys AspGly Leu Gln Ile Gly Thr Asp Val Thr Ala Asn Gln 165 170 175 Asn Lys ProIle Tyr Ala Asp Lys Thr Phe Gln Pro Glu Pro Gln Val 180 185 190 Gly GluGlu Asn Trp Gln Glu Thr Glu Asn Phe Tyr Gly Gly Arg Ala 195 200 205 LeuLys Lys Asp Thr Asn Met Lys Pro Cys Tyr Gly Ser Tyr Ala Arg 210 215 220Pro Thr Asn Glu Lys Gly Gly Gln Ala Lys Leu Lys Val Gly Asp Asp 225 230235 240 Gly Val Pro Thr Lys Glu Phe Asp Ile Asp Leu Ala Phe Phe Asp Thr245 250 255 Pro Gly Gly Thr Val Asn Gly Gln Asp Glu Tyr Lys Ala Asp IleVal 260 265 270 Met Tyr Thr Glu Asn Thr Tyr Leu Glu Thr Pro Asp Thr HisVal Val 275 280 285 Tyr Lys Pro Gly Lys Asp Asp Ala Ser Ser Glu Ile AsnLeu Val Gln 290 295 300 Gln Ser Met Pro Asn Arg Pro Asn Tyr Ile Gly PheArg Asp Asn Phe 305 310 315 320 Ile Gly Leu Met Tyr Tyr Asn Ser Thr GlyAsn Met Gly Val Leu Ala 325 330 335 Gly Gln Ala Ser Gln Leu Asn Ala ValVal Asp Leu Gln Asp Arg Asn 340 345 350 Thr Glu Leu Ser Tyr Gln Leu LeuLeu Asp Ser Leu Gly Asp Arg Thr 355 360 365 Arg Tyr Phe Ser Met Trp AsnGln Ala Val Asp Ser Tyr Asp Pro Asp 370 375 380 Val Arg Ile Ile Glu AsnHis Gly Val Glu Asp Glu Leu Pro Asn Tyr 385 390 395 400 Cys Phe Pro LeuAsp Gly Ser Gly Thr Asn Ala Ala Tyr Gln Gly Val 405 410 415 Lys Val LysAsp Gly Gln Asp Gly Asp Val Glu Ser Glu Trp Glu Asn 420 425 430 Asp AspThr Val Ala Ala Arg Asn Gln Leu Cys Lys Gly Asn Ile Phe 435 440 445 AlaMet Glu Ile Asn Leu Gln Ala Asn Leu Trp Arg Ser Phe Leu Tyr 450 455 460Ser Asn Val Ala Leu Tyr Leu Pro Asp Ser Tyr Lys Tyr Thr Pro Thr 465 470475 480 Asn Val Thr Leu Pro Thr Asn Thr Asn Thr Tyr Asp Tyr Met Asn Gly485 490 495 Arg Val Thr Pro Pro Ser Leu Val Asp Ala Tyr Leu Asn Ile GlyAla 500 505 510 Arg Trp Ser Leu Asp Pro Met Asp Asn Val Asn Pro Phe AsnHis His 515 520 525 Arg Asn Ala Gly Leu Arg Tyr Arg Ser Met Leu Leu GlyAsn Gly Arg 530 535 540 Tyr Val Pro Phe His Ile Gln Val Pro Gln Lys PhePhe Ala Ile Lys 545 550 555 560 Ser Leu Leu Leu Leu Pro Gly Ser Tyr ThrTyr Glu Trp Asn Phe Arg 565 570 575 Lys Asp Val Asn Met Ile Leu Gln SerSer Leu Gly Asn Asp Leu Arg 580 585 590 Thr Asp Gly Ala Ser Ile Ala PheThr Ser Ile Asn Leu Tyr Ala Thr 595 600 605 Phe Phe Pro Met Ala His AsnThr Ala Ser Thr Leu Glu Ala Met Leu 610 615 620 Arg Asn Asp Thr Asn AspGln Ser Phe Asn Asp Tyr Leu Ser Ala Ala 625 630 635 640 Asn Met Leu TyrPro Ile Pro Ala Asn Ala Thr Asn Val Pro Ile Ser 645 650 655 Ile Pro SerArg Asn Trp Ala Ala Phe Arg Gly Trp Ser Phe Thr Arg 660 665 670 Leu LysThr Arg Glu Thr Pro Ser Leu Gly Ser Gly Phe Asp Pro Tyr 675 680 685 PheVal Tyr Ser Gly Ser Ile Pro Tyr Leu Asp Gly Thr Phe Tyr Leu 690 695 700Asn His Thr Phe Lys Lys Val Ser Ile Thr Phe Asp Ser Ser Val Ser 705 710715 720 Trp Pro Gly Asn Asp Arg Leu Leu Thr Pro Asn Glu Phe Glu Ile Lys725 730 735 Arg Thr Val Asp Gly Glu Gly Tyr Asn Val Ala Gln Cys Asn MetThr 740 745 750 Lys Asp Trp Phe Leu Val Gln Met Leu Ala His Tyr Asn IleGly Tyr 755 760 765 Gln Gly Phe Tyr Val Pro Glu Gly Tyr Lys Asp Arg MetTyr Ser Phe 770 775 780 Phe Arg Asn Phe Gln Pro Met Ser Arg Gln Val ValAsp Glu Val Asn 785 790 795 800 Tyr Lys Asp Tyr Gln Ala Val Thr Leu AlaTyr Gln His Asn Asn Ser 805 810 815 Gly Phe Val Gly Tyr Leu Ala Pro ThrMet Arg Gln Gly Gln Pro Tyr 820 825 830 Pro Ala Asn Tyr Pro Tyr Pro LeuIle Gly Lys Ser Ala Val Ala Ser 835 840 845 Val Thr Gln Lys Lys Phe LeuCys Asp Arg Val Met Trp Arg Ile Pro 850 855 860 Phe Ser Ser Asn Phe MetSer Met Gly Ala Leu Thr Asp Leu Gly Gln 865 870 875 880 Asn Met Leu TyrAla Asn Ser Ala His Ala Leu Asp Met Asn Phe Glu 885 890 895 Val Asp ProMet Asp Glu Ser Thr Leu Leu Tyr Val Val Phe Glu Val 900 905 910 Phe AspVal Val Arg Val His Gln Pro His Arg Gly Val Ile Glu Ala 915 920 925 ValTyr Leu Arg Thr Pro Phe Ser Ala Gly Asn Ala Thr Thr 930 935 940 8 443PRT chimpanzee adenovirus serotype Pan6 8 Met Ser Lys Lys Arg Val ArgVal Asp Asp Asp Phe Asp Pro Val Tyr 1 5 10 15 Pro Tyr Asp Ala Asp AsnAla Pro Thr Val Pro Phe Ile Asn Pro Pro 20 25 30 Phe Val Ser Ser Asp GlyPhe Gln Glu Lys Pro Leu Gly Val Leu Ser 35 40 45 Leu Arg Leu Ala Asp ProVal Thr Thr Lys Asn Gly Glu Ile Thr Leu 50 55 60 Lys Leu Gly Glu Gly ValAsp Leu Asp Ser Ser Gly Lys Leu Ile Ser 65 70 75 80 Asn Thr Ala Thr LysAla Ala Ala Pro Leu Ser Ile Ser Asn Asn Thr 85 90 95 Ile Ser Leu Lys ThrAla Ala Pro Phe Tyr Asn Asn Asn Gly Thr Leu 100 105 110 Ser Leu Asn ValSer Thr Pro Leu Ala Val Phe Pro Thr Phe Asn Thr 115 120 125 Leu Gly IleSer Leu Gly Asn Gly Leu Gln Thr Ser Asn Lys Leu Leu 130 135 140 Thr ValGln Leu Thr His Pro Leu Thr Phe Ser Ser Asn Ser Ile Thr 145 150 155 160Val Lys Thr Asp Lys Gly Leu Tyr Ile Asn Ser Ser Gly Asn Arg Gly 165 170175 Leu Glu Ala Asn Ile Ser Leu Lys Arg Gly Leu Val Phe Asp Gly Asn 180185 190 Ala Ile Ala Thr Tyr Ile Gly Asn Gly Leu Asp Tyr Gly Ser Tyr Asp195 200 205 Ser Asp Gly Lys Thr Arg Pro Val Ile Thr Lys Ile Gly Ala GlyLeu 210 215 220 Asn Phe Asp Ala Asn Lys Ala Ile Ala Val Lys Leu Gly ThrGly Leu 225 230 235 240 Ser Phe Asp Ser Ala Gly Ala Leu Thr Ala Gly AsnLys Gln Asp Asp 245 250 255 Lys Leu Thr Leu Trp Thr Thr Pro Asp Pro SerPro Asn Cys Gln Leu 260 265 270 Leu Ser Asp Arg Asp Ala Lys Phe Thr LeuCys Leu Thr Lys Cys Gly 275 280 285 Ser Gln Ile Leu Gly Thr Val Ala ValAla Ala Val Thr Val Gly Ser 290 295 300 Ala Leu Asn Pro Ile Asn Asp ThrVal Lys Ser Ala Ile Val Phe Leu 305 310 315 320 Arg Phe Asp Ser Asp GlyVal Leu Met Ser Asn Ser Ser Met Val Gly 325 330 335 Asp Tyr Trp Asn PheArg Glu Gly Gln Thr Thr Gln Ser Val Ala Tyr 340 345 350 Thr Asn Ala ValGly Phe Met Pro Asn Ile Gly Ala Tyr Pro Lys Thr 355 360 365 Gln Ser LysThr Pro Lys Asn Ser Ile Val Ser Gln Val Tyr Leu Thr 370 375 380 Gly GluThr Thr Met Pro Met Thr Leu Thr Ile Thr Phe Asn Gly Thr 385 390 395 400Asp Glu Lys Asp Thr Thr Pro Val Ser Thr Tyr Ser Met Thr Phe Thr 405 410415 Trp Gln Trp Thr Gly Asp Tyr Lys Asp Lys Asn Ile Thr Phe Ala Thr 420425 430 Asn Ser Phe Ser Phe Ser Tyr Ile Ala Gln Glu 435 440 9 36535 DNAchimpanzee adenovirus serotype Pan7 CDS (13874)..(15469) L2 Penton 9catcatcaat aatatacctc aaacttttgg tgcgcgttaa tatgcaaatg agctgtttga 60atttggggag ggaggaaggt gattggccga gagacgggcg accgttaggg gcggggcggg 120tgacgttttt aatacgtggc cgtgaggcgg agccggtttg caagttctcg tgggaaaagt 180gacgtcaaac gaggtgtggt ttgaacacgg aaatactcaa ttttcccgcg ctctctgaca 240ggaaatgagg tgtttctggg cggatgcaag tgaaaacggg ccattttcgc gcgaaaactg 300aatgaggaag tgaaaatctg agtaatttcg cgtttatggc agggaggagt atttgccgag 360ggccgagtag actttgaccg attacgtggg ggtttcgatt accgtatttt tcacctaaat 420ttccgcgtac ggtgtcaaag tccggtgttt ttacgtaggc gtcagctgat cgccagggta 480tttaaacctg cgctctctag tcaagaggcc actcttgagt gccagcgagt agagttttct 540cctccgcgcc gcgagtcaga tctacacttt gaaagatgag gcacctgaga gacctgcccg 600gtaatgtttt cctggctact gggaacgaga ttctggaatt ggtggtggac gccatgatgg 660gtggcgaccc tcctgagccc cctaccccat ttgaggcgcc ttcgctgtac gatttgtatg 720atctggaggt ggatgtgccc gagaacgacc ccaacgagga ggcggtgaat gatttgttta 780gcgatgccgc gctgctggct gccgagcagg ctaatacgga ctctggctca gacagcgatt 840cctctctcca taccccgaga cccggcagag gtgagaaaaa gatccccgag cttaaagggg 900aagagctcga cctgcgctgc tatgaggaat gcttgcctcc gagcgatgat gaggaggacg 960aggaggcgat tcgagctgca tcgaaccagg gagtgaaagc tgcgggcgaa agctttagcc 1020tggactgtcc tactctgccc ggacacggct gtaagtcttg tgaatttcat cgcatgaata 1080ctggagataa gaatgtgatg tgtgccctgt gctatatgag agcttacaac cattgtgttt 1140acagtaagtg tgattaactt tagttgggaa ggcagagggt gactgggtgc tgactggttt 1200atttatgtat atgttttttt atgtgtaggt cccgtctctg acgtagatga gacccccact 1260tcagagtgca tttcatcacc cccagaaatt ggcgaggaac cgcccgaaga tattattcat 1320agaccagttg cagtgagagt caccgggcgg agagcagctg tggagagttt ggatgacttg 1380ctacagggtg gggatgaacc tttggacttg tgtacccgga aacgccccag gcactaagtg 1440ccacacatgt gtgtttactt aaggtgatgt cagtatttat agggtgtgga gtgcaataaa 1500atccgtgttg actttaagtg cgtggtttat gactcagggg tggggactgt gggtatataa 1560gcaggtgcag acctgtgtgg tcagttcaga gcaggactca tggagatctg gacggtcttg 1620gaagactttc accagactag acagctgcta gagaactcat cggagggggt ctcttacctg 1680tggagattct gcttcggtgg gcctctagct aagctagtct atagggccaa acaggattat 1740aaggatcaat ttgaggatat tttgagagag tgtcctggta tttttgactc tctcaacttg 1800ggccatcagt ctcactttaa ccagagtatt ctgagagccc ttgacttttc tactcctggc 1860agaactaccg ccgcggtagc cttttttgcc tttatccttg acaaatggag tcaagaaacc 1920catttcagca gggattaccg tctggactgc ttagcagtag ctttgtggag aacatggagg 1980tgccagcgcc tgaatgcaat ctccggctac ttgccagtac agccggtaga cacgctgagg 2040atcctgagtc tccagtcacc ccaggaacac caacgccgcc agcagccgca gcaggagcag 2100cagcaagagg aggaggagga tcgagaagag aacccgagag ccggtctgga ccctccggtg 2160gcggaggagg aggagtagct gacttgtttc ccgagctgcg ccgggtgctg actaggtctt 2220ccagtggacg ggagaggggg attaagcggg agaggcatga ggagactagc cacagaactg 2280aactgactgt cagtctgatg agccgcaggc gcccagaatc ggtgtggtgg catgaggttc 2340agtcgcaggg gatagatgag gtctcggtga tgcatgagaa atattccctg gaacaagtca 2400agacttgttg gttggagcct gaggatgatt gggaggtagc catcaggaat tatgccaagc 2460tggctctgaa gccagacaag aagtacaaga ttaccaaact gattaatatc agaaattcct 2520gctacatttc agggaatggg gccgaggtgg agatcagtac ccaggagagg gtggccttca 2580gatgttgtat gatgaatatg tacccggggg tggtgggcat ggagggagtc acctttatga 2640acgcgaggtt caggggtgat gggtataatg gggtggtctt tatggccaac accaagctga 2700cagtgcacgg atgctccttc tttgggttca ataacatgtg catcgaggcc tggggcagtg 2760tttcagtgag gggatgcagc ttttcagcca actggatggg ggtcgtgggc agaaccaaga 2820gcaaggtgtc agtgaagaaa tgcctgttcg agaggtgcca cctgggggtg atgagcgagg 2880gcgaagccaa agtcaaacac tgcgcctcta ctgagacggg ctgctttgtg ctgatcaagg 2940gcaatgccca agtcaagcat aacatgatct gtggggcctc ggatgagcgc ggctaccaga 3000tgctgacctg cgccggtggg aacagccata tgctggccac cgtgcatgtg acctcgcacc 3060cccgcaagac atggcccgag ttcgagcaca acgtcatgac ccgatgcaat gtgcacctgg 3120ggtcccgccg aggcatgttc atgccctacc agtgcaacat gcaatttgtg aaggtgctgc 3180tggagcccga tgccatgtcc agagtgagcc tgacgggggt gtttgacatg aatgtggagc 3240tgtggaaaat tctgagatat gatgaatcca agaccaggtg ccgggcctgc gaatgcggag 3300gcaagcacgc caggcttcag cccgtgtgtg tggaggtgac ggaggacctg cgacccgatc 3360atttggtgtt gtcctgcaac gggacggagt tcggctccag cggggaagaa tctgactaga 3420gtgagtagtg tttgggggag gtggagggct tgtatgaggg gcagaatgac taaaatctgt 3480gtttttctgt gtgttgcagc agcatgagcg gaagcgcctc ctttgaggga ggggtattca 3540gcccttatct gacggggcgt ctcccctcct gggcgggagt gcgtcagaat gtgatgggat 3600ccacggtgga cggccggccc gtgcagcccg cgaactcttc aaccctgacc tacgcgaccc 3660tgagctcctc gtccgtggac gcagctgccg ccgcagctgc tgcttccgcc gccagcgccg 3720tgcgcggaat ggccctgggc gccggctact acagctctct ggtggccaac tcgacttcca 3780ccaataatcc cgccagcctg aacgaggaga agctgctgct gctgatggcc cagctcgagg 3840ccctgaccca gcgcctgggc gagctgaccc agcaggtggc tcagctgcag gcggagacgc 3900gggccgcggt tgccacggtg aaaaccaaat aaaaaatgaa tcaataaata aacggagacg 3960gttgttgatt ttaacacaga gtcttgaatc tttatttgat ttttcgcgcg cggtaggccc 4020tggaccaccg gtctcgatca ttgagcaccc ggtggatttt ttccaggacc cggtagaggt 4080gggcttggat gttgaggtac atgggcatga gcccgtcccg ggggtggagg tagctccatt 4140gcagggcctc gtgctcgggg gtggtgttgt aaatcaccca gtcatagcag gggcgcaggg 4200cgtggtgctg cacgatgtcc ttgaggagga gactgatggc cacgggcagc cccttggtgt 4260aggtgttgac gaacctgttg agctgggagg gatgcatgcg gggggagatg agatgcatct 4320tggcctggat cttgagattg gcgatgttcc cgcccagatc ccgccggggg ttcatgttgt 4380gcaggaccac cagcacggtg tatccggtgc acttggggaa tttgtcatgc aacttggaag 4440ggaaggcgtg aaagaatttg gagacgccct tgtgaccgcc caggttttcc atgcactcat 4500ccatgatgat ggcgatgggc ccgtgggcgg cggcctgggc aaagacgttt cgggggtcgg 4560acacatcgta gttgtggtcc tgggtgagct cgtcataggc cattttaatg aatttggggc 4620ggagggtgcc cgactggggg acgaaggtgc cctcgatccc gggggcgtag ttgccctcgc 4680agatctgcat ctcccaggcc ttgagctcgg agggggggat catgtccacc tgcggggcga 4740tgaaaaaaac ggtttccggg gcgggggaga tgagctgggc cgaaagcagg ttccggagca 4800gctgggactt gccgcagccg gtggggccgt agatgacccc gatgaccggc tgcaggtggt 4860agttgaggga gagacagctg ccgtcctcgc ggaggagggg ggccacctcg ttcatcatct 4920cgcgcacatg catgttctcg cgcacgagtt ccgccaggag gcgctcgccc cccagcgaga 4980ggagctcttg cagcgaggcg aagtttttca gcggcttgag yccgtcggcc atgggcattt 5040tggagagggt ctgttgcaag agttccagac ggtcccagag ctcggtgatg tgctctaggg 5100catctcgatc cagcagacct cctcgtttcg cgggttgggg cgactgcggg agtagggcac 5160caggcgatgg gcgtccagcg aggccagggt ccggtccttc cagggtcgca gggtccgcgt 5220cagcgtggtc tccgtcacgg tgaaggggtg cgcgccgggc tgggcgcttg cgagggtgcg 5280cttcaggctc atccggctgg tcgagaaccg ctcccggtcg gcgccctgcg cgtcggccag 5340gtagcaattg agcatgagtt cgtagttgag cgcctcggcc gcgtggccct tggcgcggag 5400cttacctttg gaagtgtgtc cgcagacggg acagaggagg gacttgaggg cgtagagctt 5460gggggcgagg aagacggact cgggggcgta ggcgtccgcg ccgcagctgg cgcagacggt 5520ctcgcactcc acgagccagg tgaggtcggg ccggttgggg tcaaaaacga ggtttcctcc 5580gtgctttttg atgcgtttct tacctctggt ctccatgagc tcgtgtcccc gctgggtgac 5640aaagaggctg tccgtgtccc cgtagaccga ctttatgggc cggtcctcga gcggggtgcc 5700gcggtcctcg tcgtagagga accccgccca ctccgagacg aaggcccggg tccaggccag 5760cacgaaggag gccacgtggg aggggtagcg gtcgttgtcc accagcgggt ccaccttctc 5820cagggtatgc aagcacatgt ccccctcgtc cacatccagg aaggtgattg gcttgtaagt 5880gtaggccacg tgaccggggg tcccggccgg gggggtataa aagggggcgg gcccctgctc 5940gtcctcactg tcttccggat cgctgtccag gagcgccagc tgttggggta ggtattccct 6000ctcgaaggct ggcataacct cggcactcag gttgtcagtt tctagaaacg aggaggattt 6060gatattgacg gtgccgttgg agacgccttt catgagcccc tcgtccatct ggtcagaaaa 6120gacgatcttt ttgttgtcga gcttggtggc gaaggagccg tagagggcgt tggagaggag 6180cttggcgatg gagcgcatgg tctggttctt ttccttgtcg gcgcgctcct tggcggcgat 6240gttgagctgc acgtactcgc gcgccacgca cttccattcg gggaagacgg tggtgagctc 6300gtcgggcacg attctgaccc gccagccgcg gttgtgcagg gtgatgaggt ccacgctggt 6360ggccacctcg ccgcgcaggg gctcgttggt ccagcagagg cgcccgccct tgcgcgagca 6420gaaggggggc agcgggtcca gcatgagctc gtcggggggg tcggcgtcca cggtgaagat 6480gccgggcaga agctcggggt cgaagtagct gatgcaggtg tccagatcgt ccagcgccgc 6540ttgccagtcg cgcacggcca gcgcgcgctc gtaggggctg aggggcgtgc cccagggcat 6600ggggtgcgtg agcgcggagg cgtacatgcc gcagatgtcg tagacgtaga ggggctcctc 6660gaggacgccg atgtaggtgg ggtagcagcg ccccccgcgg atgctggcgc gcacgtagtc 6720gtacagctcg tgcgagggcg cgaggagccc cgtgccgagg ttggagcgtt gcggcttttc 6780ggcgcggtag acgatctggc ggaagatggc gtgggagttg gaggagatgg tgggcctctg 6840gaagatgttg aagtgggcgt ggggcaggcc gaccgagtcc ctgatgaagt gggcgtagga 6900gtcctgcagc ttggcgacga gctcggcggt gacgaggacg tccagggcgc agtagtcgag 6960ggtctcttgg atgatgtcgt acttgagctg gcccttctgc ttccacagct cgcggttgag 7020aaggaactct tcgcggtcct tccagtactc ttcgaggggg aacccgtcct gatcggcacg 7080gtaagagccc accatgtaga actggttgac ggccttgtag gcgcagcagc ccttctccac 7140ggggagggcg taagcttgtg cggccttgcg cagggaggtg tgggtgaggg cgaaggtgtc 7200gcgcaccatg accttgagga actggtgctt gaagtcgagg tcgtcgcagc cgccctgctc 7260ccagagctgg aagtccgtgc gcttcttgta ggcggggttg ggcaaagcga aagtaacatc 7320gttgaagagg atcttgcccg cgcggggcat gaagttgcga gtgatgcgga aaggctgggg 7380cacctcggcc cggttgttga tgacctgggc ggcgaggacg atctcgtcga agccgttgat 7440gttgtgcccg acgatgtaga gttccacgaa tcgcgggcgg cccttaacgt ggggcagctt 7500cttgagctcg tcgtaggtga gctcggcggg gtcgctgagc ccgtgctgct cgagggccca 7560gtcggcgacg tgggggttgg cgctgaggaa ggaagtccag agatccacgg ccagggcggt 7620ctgcaagcgg tcccggtact gacggaactg ctggcccacg gccatttttt cgggggtgac 7680gcagtagaag gtgcgggggt cgccgtgcca gcggtcccac ttgagctgga gggcgaggtc 7740gtgggcgagc tcgacgagcg gcgggtcccc ggagagtttc atgaccagca tgaaggggac 7800gagctgcttg ccgaaggacc ccatccaggt gtaggtttcc acatcgtagg tgaggaagag 7860cctttcggtg cgaggatgcg agccgatggg gaagaactgg atctcctgcc accagttgga 7920ggaatggctg ttgatgtgat ggaagtagaa atgccgacgg cgcgccgagc actcgtgctt 7980gtgtttatac aagcgtccgc agtgctcgca acgctgcacg ggatgcacgt gctgcacgag 8040ctgtacctgg gttcctttga cgaggaattt cagtgggcag tggagcgctg gcggctgcat 8100ctggtgctgt actacgtcct ggccatcggc gtggccatcg tctgcctcga tggtggtcat 8160gctgacgagc ccgcgcggga ggcaggtcca gacttcggct cggacgggtc ggagagcgag 8220gacgagggcg cgcaggccgg agctgtccag ggtcctgaga cgctgcggag tcaggtcagt 8280gggcagcggc ggcgcgcggt tgacttgcag gagcttttcc agggcgcgcg ggaggtccag 8340atggtacttg atctccacgg cgccgttggt ggcgacgtcc acggcttgca gggtcccgtg 8400cccctggggc gccaccaccg tgccccgttt cttcttgggc gctgcttcca tgccggtcag 8460aagcggcggc gaggacgcgc gccgggcggc aggggcggct cgggacccgg aggcaggggc 8520ggcaggggca cgtcggcgcc gcgcgcgggc aggttctggt actgcgcccg gagaagactg 8580gcgtgagcga cgacgcgacg gttgacgtcc tggatctgac gcctctgggt gaaggccacg 8640ggacccgtga gtttgaacct gaaagagagt tcgacagaat caatctcggt atcgttgacg 8700gcggcctgcc gcaggatctc ttgcacgtcg cccgagttgt cctggtaggc gatctcggtc 8760atgaactgct cgatctcctc ctcctgaagg tctccgcggc cggcgcgctc gacggtggcc 8820gcgaggtcgt tggagatgcg gcccatgagc tgcgagaagg cgttcatgcc ggcctcgttc 8880cagacgcggc tgtagaccac ggctccgtcg gggtcgcgcg cgcgcatgac cacctgggcg 8940aggttgagct cgacgtggcg cgtgaagacc gcgtagttgc agaggcgctg gtagaggtag 9000ttgagcgtgg tggcgatgtg ctcggtgacg aagaagtaca tgatccagcg gcggagcggc 9060atctcgctga cgtcgcccag ggcttccaag cgctccatgg cctcgtagaa gtccacggcg 9120aagttgaaaa actgggagtt gcgcgccgag acggtcaact cctcctccag aagacggatg 9180agctcagcga tggtggcgcg cacctcgcgc tcgaaggccc cggggggctc ctcttcttcc 9240atctcttcct cctccactaa catctcttct acttcctcct caggaggcgg cggcggggga 9300ggggccctgc gtcgccggcg gcgcacgggc agacggtcga tgaagcgctc gatggtctcc 9360ccgcgccggc gacgcatggt ctcggtgacg gcgcgcccgt cctcgcgggg ccgcagcgtg 9420aagacgccgc cgcgcatctc caggtggccg ccgggggggt ctccgttggg cagggagagg 9480gcgctgacga tgcatcttat caattggccc gtagggactc cgcgcaagga cctgagcgtc 9540tcgagatcca cgggatccga aaaccgctga acgaaggctt cgagccagtc gcagtcgcaa 9600ggtaggctga gcccggtttc ttgttcttcg gggatttcgg gaggcgggcg ggcgatgctg 9660ctggtgatga agttgaagta ggcggtcctg agacggcgga tggtggcgag gagcaccagg 9720tccttgggcc cggcttgctg gatgcgcaga cggtcggcca tgccccaggc gtggtcctga 9780cacctggcga ggtccttgta gtagtcctgc atgagccgct ccacgggcac ctcctcctcg 9840cccgcgcggc cgtgcatgcg cgtgagcccg aacccgcgct ggggctggac gagcgccagg 9900tcggcgacga cgcgctcggc gaggatggcc tgctgtatct gggtgagggt ggtctggaag 9960tcgtcgaagt cgacgaagcg gtggtaggct ccggtgttga tggtatagga gcagttggcc 10020atgacggacc agttgacggt ctggtggccg ggtcgcacga gctcgtggta cttgaggcgc 10080gagtaggcgc gcgtgtcgaa gatgtagtcg ttgcaggtgc gcacgaggta ctggtatccg 10140acgaggaagt gcggcggcgg ctggcggtag agcggccatc gctcggtggc gggggcgccg 10200ggcgcgaggt cctcgagcat gaggcggtgg tagccgtaga tgtacctgga catccaggtg 10260atgccggcgg cggtggtgga ggcgcgcggg aactcgcgga cgcggttcca gatgttgcgc 10320agcggcagga agtagttcat ggtggccgcg gtctggcccg tgaggcgcgc gcagtcgtgg 10380atgctctaga catacgggca aaaacgaaag cggtcagcgg ctcgactccg tggcctggag 10440gctaagcgaa cgggttgggc tgcgcgtgta ccccggttcg aatctcgaat caggctggag 10500ccgcagctaa cgtggtactg gcactcccgt ctcgacccaa gcctgctaac gaaacctcca 10560ggatacggag gcgggtcgtt ttttggcctt ggtcgctggt catgaaaaac tagtaagcgc 10620ggaaagcgac cgcccgcgat ggctcgctgc cgtagtctgg agaaagaatc gccagggttg 10680cgttgcggtg tgccccggtt cgagcctcag cgctcggcgc cggccggatt ccgcggctaa 10740cgtgggcgtg gctgccccgt cgtttccaag accccttagc cagccgactt ctccagttac 10800ggagcgagcc cctctttttc ttgtgttttt gccagatgca tcccgtactg cggcagatgc 10860gcccccaccc tccacctcaa ccgcccctac cgccgcagca gcagcaacag ccggcgcttc 10920tgcccccgcc ccagcagcag ccagccacta ccgcggcggc cgccgtgagc ggagccggcg 10980ttcagtatga cctggccttg gaagagggcg aggggctggc gcggctgggg gcgtcgtcgc 11040cggagcggca cccgcgcgtg cagatgaaaa gggacgctcg cgaggcctac gtgcccaagc 11100agaacctgtt cagagacagg agcggcgagg agcccgagga gatgcgcgcc tcccgcttcc 11160acgcggggcg ggagctgcgg cgcggcctgg accgaaagcg ggtgctgagg gacgaggatt 11220tcgaggcgga cgagctgacg gggatcagcc ccgcgcgcgc gcacgtggcc gcggccaacc 11280tggtcacggc gtacgagcag accgtgaagg aggagagcaa cttccaaaaa tccttcaaca 11340accacgtgcg cacgctgatc gcgcgcgagg aggtgaccct gggcctgatg cacctgtggg 11400acctgctgga ggccatcgtg cagaacccca cgagcaagcc gctgacggcg cagctgtttc 11460tggtggtgca gcacagtcgg gacaacgaga cgttcaggga ggcgctgctg aatatcaccg 11520agcccgaggg ccgctggctc ctggacctgg tgaacattct gcagagcatc gtggtgcagg 11580agcgcgggct gccgctgtcc gagaagctgg cggctatcaa cttctcggtg ctgagcctgg 11640gcaagtacta cgctaggaag atctacaaga ccccgtacgt gcccatagac aaggaggtga 11700agatcgacgg gttttacatg cgcatgaccc tgaaagtgct gaccctgagc gacgatctgg 11760gggtgtaccg caacgacagg atgcaccgcg cggtgagcgc cagccgccgg cgcgagctga 11820gcgaccagga gctgatgcac agcctgcagc gggccctgac cggggccggg accgaggggg 11880agagctactt tgacatgggc gcggacctgc gctggcagcc cagccgccgg gccttggaag 11940ctgccggcgg ttccccctac gtggaggagg tggacgatga ggaggaggag ggcgagtacc 12000tggaagactg atggcgcgac cgtatttttg ctagatgcag caacagccac cgcctcctga 12060tcccgcgatg cgggcggcgc tgcagagcca gccgtccggc attaactcct cggacgattg 12120gacccaggcc atgcaacgca tcatggcgct gacgacccgc aatcccgaag cctttagaca 12180gcagcctcag gccaaccggc tctcggccat cctggaggcc gtggtgccct cgcgctcgaa 12240ccccacgcac gagaaggtgc tggccatcgt gaacgcgctg gtggagaaca aggccatccg 12300cggcgacgag gccgggctgg tgtacaacgc gctgctggag cgcgtggccc gctacaacag 12360caccaacgtg cagacgaacc tggaccgcat ggtgaccgac gtgcgcgagg cggtgtcgca 12420gcgcgagcgg ttccaccgcg agtcgaacct gggctccatg gtggcgctga acgccttcct 12480gagcacgcag cccgccaacg tgccccgggg ccaggaggac tacaccaact tcatcagcgc 12540gctgcggctg atggtggccg aggtgcccca gagcgaggtg taccagtcgg ggccggacta 12600cttcttccag accagtcgcc agggcttgca gaccgtgaac ctgagccagg ctttcaagaa 12660cttgcaggga ctgtggggcg tgcaggcccc ggtcggggac cgcgcgacgg tgtcgagcct 12720gctgacgccg aactcgcgcc tgctgctgct gctggtggcg cccttcacgg acagcggcag 12780cgtgagccgc gactcgtacc tgggctacct gcttaacctg taccgcgagg ccatcgggca 12840ggcgcacgtg gacgagcaga cctaccagga gatcacccac gtgagccgcg cgctgggcca 12900ggaggacccg ggcaacctgg aggccaccct gaacttcctg ctgaccaacc ggtcgcagaa 12960gatcccgccc cagtacgcgc tgagcaccga ggaggagcgc atcctgcgct acgtgcagca 13020gagcgtgggg ctgttcctga tgcaggaggg ggccacgccc agcgccgcgc tcgacatgac 13080cgcgcgcaac atggagccca gcatgtacgc tcgcaaccgc ccgttcatca ataagctgat 13140ggactacttg catcgggcgg ccgccatgaa ctcggactac tttaccaacg ccatcttgaa 13200cccgcactgg ctcccgccgc ccgggttcta cacgggcgag tacgacatgc ccgaccccaa 13260cgacgggttc ctgtgggacg acgtggacag cagcgtgttc tcgccgcgcc ccgccaccac 13320cgtgtggaag aaagagggcg gggaccggcg gccgtcctcg gcgctgtccg gtcgcgcggg 13380tgctgccgcg gcggtgcctg aggccgccag ccccttcccg agcctgccct tttcgctgaa 13440cagcgtgcgc agcagcgagc tgggtcggct gacgcggccg cgcctgctgg gcgaggagga 13500gtacctgaac gactccttgt tgaggcccga gcgcgagaag aacttcccca ataacgggat 13560agagagcctg gtggacaaga tgagccgctg gaagacgtac gcgcacgagc acagggacga 13620gccccgagct agcagcagcg caggcacccg tagacgccag cgacacgaca ggcagcgggg 13680tctggtgtgg gacgatgagg attccgccga cgacagcagc gtgttggact tgggtgggag 13740tggtggtggt aacccgttcg ctcacttgcg cccccgtatc gggcgcctga tgtaagaatc 13800tgaaaaaata aaaaacggta ctcaccaagg ccatggcgac cagcgtgcgt tcttctctgt 13860tgtttgtagt agt atg atg agg cgc gtg tac ccg gag ggt cct cct ccc 13909 MetMet Arg Arg Val Tyr Pro Glu Gly Pro Pro Pro 1 5 10 tcg tac gag agc gtgatg cag cag gcg gtg gcg gcg gcg atg cag ccc 13957 Ser Tyr Glu Ser ValMet Gln Gln Ala Val Ala Ala Ala Met Gln Pro 15 20 25 ccg ctg gag gcg ccttac gtg ccc ccg cgg tac ctg gcg cct acg gag 14005 Pro Leu Glu Ala ProTyr Val Pro Pro Arg Tyr Leu Ala Pro Thr Glu 30 35 40 ggg cgg aac agc attcgt tac tcg gag ctg gca ccc ttg tac gat acc 14053 Gly Arg Asn Ser IleArg Tyr Ser Glu Leu Ala Pro Leu Tyr Asp Thr 45 50 55 60 acc cgg ttg tacctg gtg gac aac aag tcg gcg gac atc gcc tcg ctg 14101 Thr Arg Leu TyrLeu Val Asp Asn Lys Ser Ala Asp Ile Ala Ser Leu 65 70 75 aac tac cag aacgac cac agc aac ttc ctg acc acc gtg gtg cag aac 14149 Asn Tyr Gln AsnAsp His Ser Asn Phe Leu Thr Thr Val Val Gln Asn 80 85 90 aac gat ttc accccc acg gag gcc agc acc cag acc atc aac ttt gac 14197 Asn Asp Phe ThrPro Thr Glu Ala Ser Thr Gln Thr Ile Asn Phe Asp 95 100 105 gag cgc tcgcgg tgg ggc ggc cag ctg aaa acc atc atg cac acc aac 14245 Glu Arg SerArg Trp Gly Gly Gln Leu Lys Thr Ile Met His Thr Asn 110 115 120 atg cccaac gtg aac gag ttc atg tac agc aac aag ttc aag gcg cgg 14293 Met ProAsn Val Asn Glu Phe Met Tyr Ser Asn Lys Phe Lys Ala Arg 125 130 135 140gtg atg gtc tcg cgc aag acc ccc aat ggg gtc gcg gtg gat gag aat 14341Val Met Val Ser Arg Lys Thr Pro Asn Gly Val Ala Val Asp Glu Asn 145 150155 tat gat ggt agt cag gac gag ctg act tac gag tgg gtg gag ttt gag14389 Tyr Asp Gly Ser Gln Asp Glu Leu Thr Tyr Glu Trp Val Glu Phe Glu160 165 170 ctg ccc gag ggc aac ttc tcg gtg acc atg acc atc gat ctg atgaac 14437 Leu Pro Glu Gly Asn Phe Ser Val Thr Met Thr Ile Asp Leu MetAsn 175 180 185 aac gcc atc atc gac aac tac ttg gcg gtg ggg cgt cag aacggg gtg 14485 Asn Ala Ile Ile Asp Asn Tyr Leu Ala Val Gly Arg Gln AsnGly Val 190 195 200 ctg gag agc gac atc ggc gtg aag ttc gac acg cgc aacttc cgg ctg 14533 Leu Glu Ser Asp Ile Gly Val Lys Phe Asp Thr Arg AsnPhe Arg Leu 205 210 215 220 ggc tgg gac ccc gtg acc gag ctg gtg atg ccgggc gtg tac acc aac 14581 Gly Trp Asp Pro Val Thr Glu Leu Val Met ProGly Val Tyr Thr Asn 225 230 235 gag gcc ttc cac ccc gac atc gtc ctg ctgccc ggc tgc ggc gtg gac 14629 Glu Ala Phe His Pro Asp Ile Val Leu LeuPro Gly Cys Gly Val Asp 240 245 250 ttc acc gag agc cgc ctc agc aac ctgctg ggc atc cgc aag cgg cag 14677 Phe Thr Glu Ser Arg Leu Ser Asn LeuLeu Gly Ile Arg Lys Arg Gln 255 260 265 ccc ttc cag gag ggc ttc cag atcctg tac gag gac ctg gag ggg ggc 14725 Pro Phe Gln Glu Gly Phe Gln IleLeu Tyr Glu Asp Leu Glu Gly Gly 270 275 280 aac atc ccc gcg ctc ttg gatgtc gaa gcc tat gag aaa agc aag gag 14773 Asn Ile Pro Ala Leu Leu AspVal Glu Ala Tyr Glu Lys Ser Lys Glu 285 290 295 300 gag gcc gcc gca gcggcg acc gca gcc gtg gcc acc gcc tct acc gag 14821 Glu Ala Ala Ala AlaAla Thr Ala Ala Val Ala Thr Ala Ser Thr Glu 305 310 315 gtg cgg ggc gataat ttt gct agc gcc gcg gca gtg gcc gag gcg gct 14869 Val Arg Gly AspAsn Phe Ala Ser Ala Ala Ala Val Ala Glu Ala Ala 320 325 330 gaa acc gaaagt aag ata gtc atc cag ccg gtg gag aag gac agc aag 14917 Glu Thr GluSer Lys Ile Val Ile Gln Pro Val Glu Lys Asp Ser Lys 335 340 345 gac aggagc tac aac gtg ctc gcg gac aag aaa aac acc gcc tac cgc 14965 Asp ArgSer Tyr Asn Val Leu Ala Asp Lys Lys Asn Thr Ala Tyr Arg 350 355 360 agctgg tac ctg gcc tac aac tac ggc gac ccc gag aag ggc gtg cgc 15013 SerTrp Tyr Leu Ala Tyr Asn Tyr Gly Asp Pro Glu Lys Gly Val Arg 365 370 375380 tcc tgg acg ctg ctc acc acc tcg gac gtc acc tgc ggc gtg gag caa15061 Ser Trp Thr Leu Leu Thr Thr Ser Asp Val Thr Cys Gly Val Glu Gln385 390 395 gtc tac tgg tcg ctg ccc gac atg atg caa gac ccg gtc acc ttccgc 15109 Val Tyr Trp Ser Leu Pro Asp Met Met Gln Asp Pro Val Thr PheArg 400 405 410 tcc acg cgt caa gtt agc aac tac ccg gtg gtg ggc gcc gagctc ctg 15157 Ser Thr Arg Gln Val Ser Asn Tyr Pro Val Val Gly Ala GluLeu Leu 415 420 425 ccc gtc tac tcc aag agc ttc ttc aac gag cag gcc gtctac tcg cag 15205 Pro Val Tyr Ser Lys Ser Phe Phe Asn Glu Gln Ala ValTyr Ser Gln 430 435 440 cag ctg cgc gcc ttc acc tcg ctc acg cac gtc ttcaac cgc ttc ccc 15253 Gln Leu Arg Ala Phe Thr Ser Leu Thr His Val PheAsn Arg Phe Pro 445 450 455 460 gag aac cag atc ctc gtc cgc ccg ccc gcgccc acc att acc acc gtc 15301 Glu Asn Gln Ile Leu Val Arg Pro Pro AlaPro Thr Ile Thr Thr Val 465 470 475 agt gaa aac gtt cct gct ctc aca gatcac ggg acc ctg ccg ctg cgc 15349 Ser Glu Asn Val Pro Ala Leu Thr AspHis Gly Thr Leu Pro Leu Arg 480 485 490 agc agt atc cgg gga gtc cag cgcgtg acc gtc act gac gcc aga cgc 15397 Ser Ser Ile Arg Gly Val Gln ArgVal Thr Val Thr Asp Ala Arg Arg 495 500 505 cgc acc tgc ccc tac gtc tacaag gcc ctg ggc gta gtc gcg ccg cgc 15445 Arg Thr Cys Pro Tyr Val TyrLys Ala Leu Gly Val Val Ala Pro Arg 510 515 520 gtc ctc tcg agc cgc accttc taa aaaatgtcca ttctcatctc gcccagtaat 15499 Val Leu Ser Ser Arg ThrPhe 525 530 aacaccggtt ggggcctgcg cgcgcccagc aagatgtacg gaggcgctcgccaacgctcc 15559 acgcaacacc ccgtgcgcgt gcgcgggcac ttccgcgctc cctggggcgccctcaagggc 15619 cgcgtgcgct cgcgcaccac cgtcgacgac gtgatcgacc aggtggtggccgacgcgcgc 15679 aactacacgc ccgccgccgc gcccgcctcc accgtggacg ccgtcatcgacagcgtggtg 15739 gccgatgcgc gccggtacgc ccgcgccaag agccggcggc ggcgcatcgcccggcggcac 15799 cggagcaccc ccgccatgcg cgcggcgcga gccttgctgc gcagggccaggcgcacggga 15859 cgcagggcca tgctcagggc ggccagacgc gcggcctccg gcagcagcagcgccggcagg 15919 acccgcagac gcgcggccac ggcggcggcg gcggccatcg ccagcatgtcccgcccgcgg 15979 cgcggcaacg tgtactgggt gcgcgacgcc gccaccggtg tgcgcgtgcccgtgcgcacc 16039 cgcccccctc gcacttgaag atgctgactt cgcgatgttg atgtgtcccagcggcgagga 16099 ggatgtccaa gcgcaaatac aaggaagaga tgctccaggt catcgcgcctgagatctacg 16159 gccccgcggt gaaggaggaa agaaagcccc gcaaactgaa gcgggtcaaaaaggacaaaa 16219 aggaggagga agatgtggac ggactggtgg agtttgtgcg cgagttcgccccccggcggc 16279 gcgtgcagtg gcgcgggcgg aaagtgaaac cggtgctgcg gcccggcaccacggtggtct 16339 tcacgcccgg cgagcgttcc ggctccgcct ccaagcgctc ctacgacgaggtgtacgggg 16399 acgaggacat cctcgagcag gcggtcgagc gtctgggcga gtttgcttacggcaagcgca 16459 gccgccccgc gcccttgaaa gaggaggcgg tgtccatccc gctggaccacggcaacccca 16519 cgccgagcct gaagccggtg accctgcagc aggtgctgcc gagcgcggcgccgcgccggg 16579 gcttcaagcg cgagggcggc gaggatctgt acccgaccat gcagctgatggtgcccaagc 16639 gccagaagct ggaggacgtg ctggagcaca tgaaggtgga ccccgaggtgcagcccgagg 16699 tcaaggtgcg gcccatcaag caggtggccc cgggcctggg cgtgcagaccgtggacatca 16759 agatccccac ggagcccatg gaaacgcaga ccgagcccgt gaagcccagcaccagcacca 16819 tggaggtgca gacggatccc tggatgccgg cgccggcttc caccactcgccgaagacgca 16879 agtacggcgc ggccagcctg ctgatgccca actacgcgct gcatccttccatcatcccca 16939 cgccgggcta ccgcggcacg cgcttctacc gcggctacac cagcagccgccgcaagacca 16999 ccacccgccg ccgccgtcgt cgcacccgcc gcagcagcac cgcgacttccgccgccgccc 17059 tggtgcggag agtgtaccgc agcgggcgcg agcctctgac cctgccgcgcgcgcgctacc 17119 acccgagcat cgccatttaa ctctgccgtc gcctcctact tgcagatatggccctcacat 17179 gccgcctccg cgtccccatt acgggctacc gaggaagaaa gccgcgccgtagaaggctga 17239 cggggaacgg gctgcgtcgc catcaccacc ggcggcggcg cgccatcagcaagcggttgg 17299 ggggaggctt cctgcccgcg ctgatcccca tcatcgccgc ggcgatcggggcgatccccg 17359 gcatagcttc cgtggcggtg caggcctctc agcgccactg agacacagcttggaaaattt 17419 gtaataaaaa aatggactga cgctcctggt cctgtgatgt gtgtttttagatggaagaca 17479 tcaatttttc gtccctggca ccgcgacacg gcacgcggcc gtttatgggcacctggagcg 17539 acatcggcaa cagccaactg aacgggggcg ccttcaattg gagcagtctctggagcgggc 17599 ttaagaattt cgggtccacg ctcaaaacct atggcaacaa ggcgtggaacagcagcacag 17659 ggcaggcgct gagggaaaag ctgaaagagc agaacttcca gcagaaggtggtcgatggcc 17719 tggcctcggg catcaacggg gtggtggacc tggccaacca ggccgtgcagaaacagatca 17779 acagccgcct ggacgcggtc ccgcccgcgg ggtccgtgga gatgccccaggtggaggagg 17839 agctgcctcc cctggacaag cgcggcgaca agcgaccgcg tcccgacgcggaggagacgc 17899 tgctgacgca cacggacgag ccgcccccgt acgaggaggc ggtgaaactgggtctgccca 17959 ccacgcggcc cgtggcgcct ctggccaccg gggtgctgaa acccagcagcagcagccagc 18019 ccgcgaccct ggacttgcct ccgcctgctt cccgcccctc cacagtggctaagcccctgc 18079 cgccggtggc cgtcgcgtcg cgcgcccccc gaggccgccc ccaggcgaactggcagagca 18139 ctctgaacag catcgtgggt ctgggagtgc agagtgtgaa gcgccgccgctgctattaaa 18199 agacactgta gcgcttaact tgcttgtctg tgtgtatatg tatgtccgccgaccagaagg 18259 aggaagaggc gcgtcgccga gttgcaag atg gcc acc cca tcg atgctg ccc 18311 Met Ala Thr Pro Ser Met Leu Pro 535 cag tgg gcg tac atgcac atc gcc gga cag gac gct tcg gag tac ctg 18359 Gln Trp Ala Tyr MetHis Ile Ala Gly Gln Asp Ala Ser Glu Tyr Leu 540 545 550 555 agt ccg ggtctg gtg cag ttc gcc cgc gcc aca gac acc tac ttc agt 18407 Ser Pro GlyLeu Val Gln Phe Ala Arg Ala Thr Asp Thr Tyr Phe Ser 560 565 570 ctg gggaac aag ttt agg aac ccc acg gtg gcg ccc acg cac gat gtg 18455 Leu GlyAsn Lys Phe Arg Asn Pro Thr Val Ala Pro Thr His Asp Val 575 580 585 accacc gac cgc agc cag cgg ctg acg ctg cgc ttc gtg ccc gtg gac 18503 ThrThr Asp Arg Ser Gln Arg Leu Thr Leu Arg Phe Val Pro Val Asp 590 595 600cgc gag gac aac acc tac tcg tac aaa gtg cgc tac acg ctg gcc gtg 18551Arg Glu Asp Asn Thr Tyr Ser Tyr Lys Val Arg Tyr Thr Leu Ala Val 605 610615 ggc gac aac cgc gtg ctg gac atg gcc agc acc tac ttt gac atc cgc18599 Gly Asp Asn Arg Val Leu Asp Met Ala Ser Thr Tyr Phe Asp Ile Arg620 625 630 635 ggc gtg ctg gat cgg ggg ccc agc ttc aaa ccc tac tcc ggcacc gcc 18647 Gly Val Leu Asp Arg Gly Pro Ser Phe Lys Pro Tyr Ser GlyThr Ala 640 645 650 tac aac agc ctg gct ccc aag gga gcg ccc aac act tgccag tgg aca 18695 Tyr Asn Ser Leu Ala Pro Lys Gly Ala Pro Asn Thr CysGln Trp Thr 655 660 665 tat aaa gct ggt gat act gat aca gaa aaa acc tataca tat gga aat 18743 Tyr Lys Ala Gly Asp Thr Asp Thr Glu Lys Thr TyrThr Tyr Gly Asn 670 675 680 gca cct gtg caa ggc att agc att aca aag gatggt att caa ctt gga 18791 Ala Pro Val Gln Gly Ile Ser Ile Thr Lys AspGly Ile Gln Leu Gly 685 690 695 act gac agc gat ggt cag gca atc tat gcagac gaa act tat caa cca 18839 Thr Asp Ser Asp Gly Gln Ala Ile Tyr AlaAsp Glu Thr Tyr Gln Pro 700 705 710 715 gag cct caa gtg ggt gat gct gaatgg cat gac atc act ggt act gat 18887 Glu Pro Gln Val Gly Asp Ala GluTrp His Asp Ile Thr Gly Thr Asp 720 725 730 gaa aaa tat gga ggc aga gctctt aag cct gac acc aaa atg aag cct 18935 Glu Lys Tyr Gly Gly Arg AlaLeu Lys Pro Asp Thr Lys Met Lys Pro 735 740 745 tgc tat ggt tct ttt gccaag cct acc aat aaa gaa gga ggc cag gca 18983 Cys Tyr Gly Ser Phe AlaLys Pro Thr Asn Lys Glu Gly Gly Gln Ala 750 755 760 aat gtg aaa acc gaaaca ggc ggt acc aaa gaa tat gac att gac atg 19031 Asn Val Lys Thr GluThr Gly Gly Thr Lys Glu Tyr Asp Ile Asp Met 765 770 775 gca ttc ttc gataat cga agt gca gct gcc gcc ggc cta gcc cca gaa 19079 Ala Phe Phe AspAsn Arg Ser Ala Ala Ala Ala Gly Leu Ala Pro Glu 780 785 790 795 att gttttg tat act gag aat gtg gat ctg gaa act cca gat acc cat 19127 Ile ValLeu Tyr Thr Glu Asn Val Asp Leu Glu Thr Pro Asp Thr His 800 805 810 attgta tac aag gca ggt aca gat gac agt agc tct tct atc aat ttg 19175 IleVal Tyr Lys Ala Gly Thr Asp Asp Ser Ser Ser Ser Ile Asn Leu 815 820 825ggt cag cag tcc atg ccc aac aga ccc aac tac att ggc ttc aga gac 19223Gly Gln Gln Ser Met Pro Asn Arg Pro Asn Tyr Ile Gly Phe Arg Asp 830 835840 aac ttt atc ggt ctg atg tac tac aac agc act ggc aat atg ggt gta19271 Asn Phe Ile Gly Leu Met Tyr Tyr Asn Ser Thr Gly Asn Met Gly Val845 850 855 ctg gct gga cag gcc tcc cag ctg aat gct gtg gtg gac ttg caggac 19319 Leu Ala Gly Gln Ala Ser Gln Leu Asn Ala Val Val Asp Leu GlnAsp 860 865 870 875 aga aac acc gaa ctg tcc tac cag ctc ttg ctt gac tctctg ggt gac 19367 Arg Asn Thr Glu Leu Ser Tyr Gln Leu Leu Leu Asp SerLeu Gly Asp 880 885 890 aga acc agg tat ttc agt atg tgg aat cag gcg gtggac agt tat gac 19415 Arg Thr Arg Tyr Phe Ser Met Trp Asn Gln Ala ValAsp Ser Tyr Asp 895 900 905 ccc gat gtg cgc att att gaa aat cac ggt gtggag gat gaa ctt cct 19463 Pro Asp Val Arg Ile Ile Glu Asn His Gly ValGlu Asp Glu Leu Pro 910 915 920 aac tat tgc ttc ccc ctg gat gct gtg ggtaga act gat act tac cag 19511 Asn Tyr Cys Phe Pro Leu Asp Ala Val GlyArg Thr Asp Thr Tyr Gln 925 930 935 gga att aag gcc aat ggt gat aat caaacc acc tgg acc aaa gat gat 19559 Gly Ile Lys Ala Asn Gly Asp Asn GlnThr Thr Trp Thr Lys Asp Asp 940 945 950 955 act gtt aat gat gct aat gaattg ggc aag ggc aat cct ttc gcc atg 19607 Thr Val Asn Asp Ala Asn GluLeu Gly Lys Gly Asn Pro Phe Ala Met 960 965 970 gag atc aac atc cag gccaac ctg tgg cgg aac ttc ctc tac gcg aac 19655 Glu Ile Asn Ile Gln AlaAsn Leu Trp Arg Asn Phe Leu Tyr Ala Asn 975 980 985 gtg gcg ctg tac ctgccc gac tcc tac aag tac acg ccg gcc aac atc 19703 Val Ala Leu Tyr LeuPro Asp Ser Tyr Lys Tyr Thr Pro Ala Asn Ile 990 995 1000 acg ctg ccc accaac acc aac acc tac gat tac atg aac ggc cgc 19748 Thr Leu Pro Thr AsnThr Asn Thr Tyr Asp Tyr Met Asn Gly Arg 1005 1010 1015 gtg gtg gcg ccctcg ctg gtg gac gcc tac atc aac atc ggg gcg 19793 Val Val Ala Pro SerLeu Val Asp Ala Tyr Ile Asn Ile Gly Ala 1020 1025 1030 cgc tgg tcg ctggac ccc atg gac aac gtc aac ccc ttc aac cac 19838 Arg Trp Ser Leu AspPro Met Asp Asn Val Asn Pro Phe Asn His 1035 1040 1045 cac cgc aac gcgggc ctg cga tac cgc tcc atg ctc ctg ggc aac 19883 His Arg Asn Ala GlyLeu Arg Tyr Arg Ser Met Leu Leu Gly Asn 1050 1055 1060 ggg cgc tac gtgccc ttc cac atc cag gtg ccc caa aag ttt ttc 19928 Gly Arg Tyr Val ProPhe His Ile Gln Val Pro Gln Lys Phe Phe 1065 1070 1075 gcc atc aag agcctc ctg ctc ctg ccc ggg tcc tac acc tac gag 19973 Ala Ile Lys Ser LeuLeu Leu Leu Pro Gly Ser Tyr Thr Tyr Glu 1080 1085 1090 tgg aac ttc cgcaag gac gtc aac atg atc ctg cag agc tcc ctc 20018 Trp Asn Phe Arg LysAsp Val Asn Met Ile Leu Gln Ser Ser Leu 1095 1100 1105 ggc aac gac ctgcgc acg gac ggg gcc tcc atc gcc ttc acc agc 20063 Gly Asn Asp Leu ArgThr Asp Gly Ala Ser Ile Ala Phe Thr Ser 1110 1115 1120 atc aac ctc tacgcc acc ttc ttc ccc atg gcg cac aac acc gcc 20108 Ile Asn Leu Tyr AlaThr Phe Phe Pro Met Ala His Asn Thr Ala 1125 1130 1135 tcc acg ctc gaggcc atg ctg cgc aac gac acc aac gac cag tcc 20153 Ser Thr Leu Glu AlaMet Leu Arg Asn Asp Thr Asn Asp Gln Ser 1140 1145 1150 ttc aac gac tacctc tcg gcg gcc aac atg ctc tac ccc atc ccg 20198 Phe Asn Asp Tyr LeuSer Ala Ala Asn Met Leu Tyr Pro Ile Pro 1155 1160 1165 gcc aac gcc accaac gtg ccc atc tcc atc ccc tcg cgc aac tgg 20243 Ala Asn Ala Thr AsnVal Pro Ile Ser Ile Pro Ser Arg Asn Trp 1170 1175 1180 gcc gcc ttc cgcggc tgg tcc ttc acg cgc ctc aag acc cgc gag 20288 Ala Ala Phe Arg GlyTrp Ser Phe Thr Arg Leu Lys Thr Arg Glu 1185 1190 1195 acg ccc tcg ctcggc tcc ggg ttc gac ccc tac ttc gtc tac tcg 20333 Thr Pro Ser Leu GlySer Gly Phe Asp Pro Tyr Phe Val Tyr Ser 1200 1205 1210 ggc tcc atc ccctac ctc gac ggc acc ttc tac ctc aac cac acc 20378 Gly Ser Ile Pro TyrLeu Asp Gly Thr Phe Tyr Leu Asn His Thr 1215 1220 1225 ttc aag aag gtctcc atc acc ttc gac tcc tcc gtc agc tgg ccc 20423 Phe Lys Lys Val SerIle Thr Phe Asp Ser Ser Val Ser Trp Pro 1230 1235 1240 ggc aac gac cgcctc ctg acg ccc aac gag ttc gaa atc aag cgc 20468 Gly Asn Asp Arg LeuLeu Thr Pro Asn Glu Phe Glu Ile Lys Arg 1245 1250 1255 acc gtc gac ggagag ggg tac aac gtg gcc cag tgc aac atg acc 20513 Thr Val Asp Gly GluGly Tyr Asn Val Ala Gln Cys Asn Met Thr 1260 1265 1270 aag gac tgg ttcctg gtc cag atg ctg gcc cac tac aac atc ggc 20558 Lys Asp Trp Phe LeuVal Gln Met Leu Ala His Tyr Asn Ile Gly 1275 1280 1285 tac cag ggc ttctac gtg ccc gag ggc tac aag gac cgc atg tac 20603 Tyr Gln Gly Phe TyrVal Pro Glu Gly Tyr Lys Asp Arg Met Tyr 1290 1295 1300 tcc ttc ttc cgcaac ttc cag ccc atg agc cgc cag gtc gtg gac 20648 Ser Phe Phe Arg AsnPhe Gln Pro Met Ser Arg Gln Val Val Asp 1305 1310 1315 gag gtc aac tacaag gac tac cag gcc gtc acc ctg gcc tac cag 20693 Glu Val Asn Tyr LysAsp Tyr Gln Ala Val Thr Leu Ala Tyr Gln 1320 1325 1330 cac aac aac tcgggc ttc gtc ggc tac ctc gcg ccc acc atg cgc 20738 His Asn Asn Ser GlyPhe Val Gly Tyr Leu Ala Pro Thr Met Arg 1335 1340 1345 cag ggc cag ccctac ccc gcc aac tac ccc tac ccg ctc atc ggc 20783 Gln Gly Gln Pro TyrPro Ala Asn Tyr Pro Tyr Pro Leu Ile Gly 1350 1355 1360 aag agc gcc gtcgcc agc gtc acc cag aaa aag ttc ctc tgc gac 20828 Lys Ser Ala Val AlaSer Val Thr Gln Lys Lys Phe Leu Cys Asp 1365 1370 1375 cgg gtc atg tggcgc atc ccc ttc tcc agc aac ttc atg tcc atg 20873 Arg Val Met Trp ArgIle Pro Phe Ser Ser Asn Phe Met Ser Met 1380 1385 1390 ggc gcg ctc accgac ctc ggc cag aac atg ctc tac gcc aac tcc 20918 Gly Ala Leu Thr AspLeu Gly Gln Asn Met Leu Tyr Ala Asn Ser 1395 1400 1405 gcc cac gcg ctagac atg aat ttc gaa gtc gac ccc atg gat gag 20963 Ala His Ala Leu AspMet Asn Phe Glu Val Asp Pro Met Asp Glu 1410 1415 1420 tcc acc ctt ctctat gtt gtc ttc gaa gtc ttc gac gtc gtc cga 21008 Ser Thr Leu Leu TyrVal Val Phe Glu Val Phe Asp Val Val Arg 1425 1430 1435 gtg cac cag ccccac cgc ggc gtc atc gag gcc gtc tac ctg cgc 21053 Val His Gln Pro HisArg Gly Val Ile Glu Ala Val Tyr Leu Arg 1440 1445 1450 acg ccc ttc tcggcc ggc aac gcc acc acc taa gcctcttgct 21096 Thr Pro Phe Ser Ala Gly AsnAla Thr Thr 1455 1460 tcttgcaaga tgacggcctg cgcgggctcc ggcgagcaggagctcagggc catcctccgc 21156 gacctgggct gcgggccctg cttcctgggc accttcgacaagcgcttccc gggattcatg 21216 gccccgcaca agctggcctg cgccatcgtc aacacggccggccgcgagac cgggggcgag 21276 cactggctgg ccttcgcctg gaacccgcgc tcccacacctgctacctctt cgaccccttc 21336 gggttctcgg acgagcgcct caagcagatc taccagttcgagtacgaggg cctgctgcgt 21396 cgcagcgccc tggccaccga ggaccgctgc gtcaccctggaaaagtccac ccagaccgtg 21456 cagggtccgc gctcggccgc ctgcgggctc ttctgctgcatgttcctgca cgccttcgtg 21516 cactggcccg accgccccat ggacaagaac cccaccatgaacttgctgac gggggtgccc 21576 aacggcatgc tccagtcgcc ccaggtggaa cccaccctgcgccgcaacca ggaggcgctc 21636 taccgcttcc tcaacgccca ctccgcctac tttcgctcccaccgcgcgcg catcgagaag 21696 gccaccgcct tcgaccgcat gaatcaagac atgtaatccggtgtgtgtat gtgaatgctt 21756 tattcatcat aataaacagc acatgtttat gccaccttctctgaggctct gactttattt 21816 agaaatcgaa ggggttctgc cggctctcgg catggcccgcgggcagggat acgttgcgga 21876 actggtactt gggcagccac ttgaactcgg ggatcagcagcttcggcacg gggaggtcgg 21936 ggaacgagtc gctccacagc ttgcgcgtga gttgcagggcgcccagcagg tcgggcgcgg 21996 agatcttgaa atcgcagttg ggacccgcgt tctgcgcgcgagagttacgg tacacggggt 22056 tgcagcactg gaacaccatc agggccgggt gcttcacgctcgccagcacc gtcgcgtcgg 22116 tgatgccctc cacgtccaga tcctcggcgt tggccatcccgaagggggtc atcttgcagg 22176 tctgccgccc catgctgggc acgcagccgg gcttgtggttgcaatcgcag tgcaggggga 22236 tcagcatcat ctgggcctgc tcggagctca tgcccgggtacatggccttc atgaaagcct 22296 ccagctggcg gaaggcctgc tgcgccttgc cgccctcggtgaagaagacc ccgcaggact 22356 tgctagagaa ctggttggtg gcgcagccag cgtcgtgcacgcagcagcgc gcgtcgttgt 22416 tggccagctg caccacgctg cgcccccagc ggttctgggtgatcttggcc cggtcggggt 22476 tctccttcag cgcgcgctgc ccgttctcgc tcgccacatccatctcgatc gtgtgctcct 22536 tctggatcat cacggtcccg tgcaggcacc gcagcttgccctcggcctcg gtgcacccgt 22596 gcagccacag cgcgcagccg gtgctctccc agttcttgtgggcgatctgg gagtgcgagt 22656 gcacgaagcc ctgcaggaag cggcccatca tcgtggtcagggtcttgttg ctggtgaagg 22716 tcagcggaat gccgcggtgc tcctcgttca catacaggtggcagatacgg cggtacacct 22776 cgccctgctc gggcatcagc tggaaggcgg acttcaggtcgctctccacg cggtaccggt 22836 ccatcagcag cgtcatcact tccatgccct tctcccaggccgaaacgatc ggcaggctca 22896 gggggttctt caccgttgtc atcttagtcg ccgccgccgaagtcaggggg tcgttctcgt 22956 ccagggtctc aaacactcgc ttgccgtcct tctcggtgatgcgcacgggg ggaaagctga 23016 agcccacggc cgccagctcc tcctcggcct gcctttcgtcctcgctgtcc tggctgatgt 23076 cttgcaaagg cacatgcttg gtcttgcggg gtttctttttgggcggcaga ggcggcggcg 23136 gagacgtgct gggcgagcgc gagttctcgc tcaccacgactatttcttct ccttggccgt 23196 cgtccgagac cacgcggcgg taggcatgcc tcttctggggcagaggcgga ggcgacgggc 23256 tctcgcggtt cggcgggcgg ctggcagagc cccttccgcgttcgggggtg cgctcctggc 23316 ggcgctgctc tgactgactt cctccgcggc cggccattgtgttctcctag ggagcaagca 23376 tggagactca gccatcgtcg ccaacatcgc catctgcccccgccgccgcc gacgagaacc 23436 agcagcagca gaatgaaagc ttaaccgccc cgccgcccagccccacctcc gacgccgcag 23496 ccccagacat gcaagagatg gaggaatcca tcgagattgacctgggctac gtgacgcccg 23556 cggagcacga ggaggagctg gcagcgcgct tttcagccccggaagagaac caccaagagc 23616 agccagagca ggaagcagag agcgagcaga accaggctgggctcgagcat ggcgactacc 23676 tgagcggggc agaggacgtg ctcatcaagc atctggcccgccaatgcatc atcgtcaagg 23736 acgcgctgct cgaccgcgcc gaggtgcccc tcagcgtggcggagctcagc cgcgcctacg 23796 agcgcaacct cttctcgccg cgcgtgcccc ccaagcgccagcccaacggc acctgcgagc 23856 ccaacccgcg cctcaacttc tacccggtct tcgcggtgcccgaggccctg gccacctacc 23916 acctcttttt caagaaccaa aggatccccg tctcctgccgcgccaaccgc acccgcgccg 23976 acgccctgct caacctgggc cccggcgccc gcctacctgatatcgcctcc ttggaagagg 24036 ttcccaagat cttcgagggt ctgggcagcg acgagactcgggccgcgaac gctctgcaag 24096 gaagcggaga ggagcatgag caccacagcg ccctggtggagttggaaggc gacaacgcgc 24156 gcctggcggt cctcaagcgc acggtcgagc tgacccacttcgcctacccg gcgctcaacc 24216 tgccccccaa ggtcatgagc gccgtcatgg accaggtgctcatcaagcgc gcctcgcccc 24276 tctcggagga ggagatgcag gaccccgaga gctcggacgagggcaagccc gtggtcagcg 24336 acgagcagct ggcgcgctgg ctgggagcga gtagcaccccccagagcctg gaagagcggc 24396 gcaagctcat gatggccgtg gtcctggtga ccgtggagctggagtgtctg cgccgcttct 24456 tcgccgacgc ggagaccctg cgcaaggtcg aggagaacctgcactacctc ttcagacacg 24516 ggttcgtgcg ccaggcctgc aagatctcca acgtggagctgaccaacctg gtctcctaca 24576 tgggcatcct gcacgagaac cgcctggggc agaacgtgctgcacaccacc ctgcgcgggg 24636 aggcccgccg cgactacatc cgcgactgcg tctacctgtacctctgccac acctggcaga 24696 cgggcatggg cgtgtggcag cagtgcctgg aggagcagaacctgaaagag ctctgcaagc 24756 tcctgcagaa gaacctcaag gccctgtgga ccgggttcgacgagcgcacc accgccgcgg 24816 acctggccga cctcatcttc cccgagcgcc tgcggctgacgctgcgcaac gggctgcccg 24876 actttatgag ccaaagcatg ttgcaaaact ttcgctctttcatcctcgaa cgctccggga 24936 tcctgcccgc cacctgctcc gcgctgccct cggacttcgtgccgctgacc ttccgcgagt 24996 gccccccgcc gctctggagc cactgctacc tgctgcgcctggccaactac ctggcctacc 25056 actcggacgt gatcgaggac gtcagcggcg agggcctgctcgagtgccac tgccgctgca 25116 acctctgcac gccgcaccgc tccctggcct gcaacccccagctgctgagc gagacccaga 25176 tcatcggcac cttcgagttg caaggccccg gcgagggcaaggggggtctg aaactcaccc 25236 cggggctgtg gacctcggcc tacttgcgca agttcgtgcccgaggactac catcccttcg 25296 agatcaggtt ctacgaggac caatcccagc cgcccaaggccgagctgtcg gcctgcgtca 25356 tcacccaggg ggccatcctg gcccaattgc aagccatccagaaatcccgc caagaatttc 25416 tgctgaaaaa gggccacggg gtctacttgg acccccagaccggagaggag ctcaacccca 25476 gcttccccca ggatgccccg aggaagcagc aagaagctgaaagtggagct gccgccgccg 25536 ccggaggatt tggaggaaga ctgggagagc agtcaggcagaggaggagga gatggaagac 25596 tgggacagca ctcaggcaga ggaggacagc ctgcaagacagtctggagga ggaagacgag 25656 gtggaggagg cagaggaaga agcagccgcc gccagaccgtcgtcctcggc ggaggaggag 25716 aaagcaagca gcacggatac catctccgct ccgggtcggggtcgcggcgg ccgggcccac 25776 agtagatggg acgagaccgg gcgcttcccg aaccccaccacccagaccgg taagaaggag 25836 cggcagggat acaagtcctg gcgggggcac aaaaacgccatcgtctcctg cttgcaagcc 25896 tgcgggggca acatctcctt cacccggcgc tacctgctcttccaccgcgg ggtgaacttc 25956 ccccgcaaca tcttgcatta ctaccgtcac ctccacagcccctactactg tttccaagaa 26016 gaggcagaaa cccagcagca gcagcagcag cagaaaaccagcggcagcag ctagaaaatc 26076 cacagcggcg gcaggtggac tgaggatcgc ggcgaacgagccggcgcaga cccgggagct 26136 gaggaaccgg atctttccca ccctctatgc catcttccagcagagtcggg ggcaagagca 26196 ggaactgaaa gtcaagaacc gttctctgcg ctcgctcacccgcagttgtc tgtatcacaa 26256 gagcgaagac caacttcagc gcactctcga ggacgccgaggctctcttca acaagtactg 26316 cgcgctcact cttaaagagt agcccgcgcc cgcccacacacggaaaaagg cgggaattac 26376 gtcaccacct gcgcccttcg cccgaccatc atcatgagcaaagagattcc cacgccttac 26436 atgtggagct accagcccca gatgggcctg gccgccggcgccgcccagga ctactccacc 26496 cgcatgaact ggctcagtgc cgggcccgcg atgatctcacgggtgaatga catccgcgcc 26556 caccgaaacc agatactcct agaacagtca gcgatcaccgccacgccccg ccatcacctt 26616 aatccgcgta attggcccgc cgccctggtg taccaggaaattccccagcc cacgaccgta 26676 ctacttccgc gagacgccca ggccgaagtc cagctgactaactcaggtgt ccagctggcc 26736 ggcggcgccg ccctgtgtcg tcaccgcccc gctcagggtataaagcggct ggtgatccga 26796 ggcagaggca cacagctcaa cgacgaggtg gtgagctcttcgctgggtct gcgacctgac 26856 ggagtcttcc aactcgccgg atcggggaga tcttccttcacgcctcgtca ggccgtcctg 26916 actttggaga gttcgtcctc gcagccccgc tcgggtggcatcggcactct ccagttcgtg 26976 gaggagttca ctccctcggt ctacttcaac cccttctccggctcccccgg ccactacccg 27036 gacgagttca tcccgaactt cgacgccatc agcgagtcggtggacggcta cgattgaatg 27096 tcccatggtg gcgcggctga cctagctcgg cttcgacacctggaccactg ccgccgcttc 27156 cgctgcttcg ctcgggatct cgccgagttt gcctactttgagctgcccga ggagcaccct 27216 cagggcccgg cccacggagt gcggatcgtc gtcgaagggggtctcgactc ccacctgctt 27276 cggatcttca gccagcgtcc gatcctggcc gagcgcgagcaaggacagac ccttctgacc 27336 ctgtactgca tctgcaacca ccccggcctg catgaaagtctttgttgtct gctgtgtact 27396 gagtataata aaagctgaga tcagcgacta ctccggacttccgtgtgttc ctgctatcaa 27456 ccagtccctg ttcttcaccg ggaacgagac cgagctccagctccagtgta agccccacaa 27516 gaagtacctc acctggctgt tccagggctc tccgatcgccgttgtcaacc actgcgacaa 27576 cgacggagtc ctgctgagcg gccctgccaa ccttactttttccacccgca gaagcaagct 27636 ccagctcttc caacccttcc tccccgggac ctatcagtgcgtctcgggac cctgccatca 27696 caccttccac ctgatcccga ataccacagc gtcgctccccgctactaaca accaaactac 27756 ccaccaacgc caccgtcgcg acctttcctc tgggtctaataccactaccg gaggtgagct 27816 ccgaggtcga ccaacctctg ggatttacta cggcccctgggaggtggtag ggttaatagc 27876 gctaggccta gttgcgggtg ggcttttggc tctctgctacctatacctcc cttgctgttc 27936 gtacttagtg gtgctgtgtt gctggtttaa gaaatggggaagatcaccct agtgagctgc 27996 ggtgtgctgg tggcggtggt gctttcgatt gtgggactgggcggcgcggc tgtagtgaag 28056 gagaaggccg atccctgctt gcatttcaat cccgacaaatgccagctgag ttttcagccc 28116 gatggcaatc ggtgcgcggt gctgatcaag tgcggatgggaatgcgagaa cgtgagaatc 28176 gagtacaata acaagactcg gaacaatact ctcgcgtccgtgtggcagcc cggggacccc 28236 gagtggtaca ccgtctctgt ccccggtgct gacggctccccgcgcaccgt gaataatact 28296 ttcatttttg cgcacatgtg cgacacggtc atgtggatgagcaagcagta cgatatgtgg 28356 ccccccacga aggagaacat cgtggtcttc tccatcgcttacagcgtgtg cacggcgcta 28416 atcaccgcta tcgtgtgcct gagcattcac atgctcatcgctattcgccc cagaaataat 28476 gccgaaaaag aaaaacagcc ataacacgtt ttttcacacacctttttcag accatggcct 28536 ctgttaaatt tttgctttta tttgccagtc tcattgccgtcattcatgga atgagtaatg 28596 agaaaattac tatttacact ggcactaatc acacattgaaaggtccagaa aaagccacag 28656 aagtttcatg gtattgttat tttaatgaat cagatgtatctactgaactc tgtggaaaca 28716 ataacaaaaa aaatgagagc attactctca tcaagtttcaatgtggatct gacttaaccc 28776 taattaacat cactagagac tatgtaggta tgtattatggaactacagca ggcatttcgg 28836 acatggaatt ttatcaagtt tctgtgtctg aacccaccacgcctagaatg accacaacca 28896 caaaaactac acctgttacc actatacagc tcactaccaatggctttctt gccatgcttc 28956 aagtggctga aaatagcacc agcattcaac ccaccccacccagtgaggaa attcccagat 29016 ccatgattgg cattattgtt gctgtagtgg tgtgcatgttgatcatcgcc ttgtgcatgg 29076 tgtactatgc cttctgctac agaaagcaca gactgaacgacaagctggaa cacttactaa 29136 gtgttgaatt ttaatttttt agaaccatga agatcctaggccttttagtt ttttctatca 29196 ttacctctgc tctatgcaat tctgacaatg aggacgttactgtcgttgtc ggatcaaatt 29256 atacactaaa aggtccagca aaaggtatgc tttcgtggtattgttggttc ggaactgacg 29316 agcaacagac agaactttgc aatgctcaaa aaggcaaaacctcaaattct aaaatctcta 29376 attatcaatg caatggcact gacttagtat tgctcaatgtcacgaaagca tatgctggca 29436 gttacacctg ccctggagat gatgccgaca atatgattttttacaaagtg gaagtggttg 29496 atcccactac tccaccgccc accaccacaa ctactcataccacacacaca gaacaaacac 29556 cagaggcagc agaagcagag ttggccttcc aggttcacggagattccttt gctgtcaata 29616 cccctacacc cgatcagcgg tgtccggggc tgctcgtcagcggcattgtc ggtgtgcttt 29676 cgggattagc agtcataatc atctgcatgt tcatttttgcttgctgctat agaaggcttt 29736 accgacaaaa atcagaccca ctgctgaacc tctatgtttaattttttcca gagccatgaa 29796 ggcagttagc gctctagttt tttgttcttt gattggcattgtttttagtg ctgggttttt 29856 gaaaaatctt accatttatg aaggtgagaa tgccactctagtgggcatca gtggtcaaaa 29916 tgtcagctgg ctaaaatacc atctagatgg gtggaaagacatttgcgatt ggaatgtcac 29976 tgtgtataca tgtaatggag ttaacctcac cattactaatgccacccaag atcagaatgg 30036 taggtttaag ggccagagtt tcactagaaa taatgggtatgaatcccata acatgtttat 30096 ctatgacgtc actgtcatca gaaatgagac tgccaccaccacacagatgc ccactacaca 30156 cagttctacc actactacca tgcaaaccac acagacaaccactacatcaa ctcagcatat 30216 gaccaccact acagcagcaa agccaagtag tgcagcgcctcagccccagg ctttggcttt 30276 gaaagctgca caacctagta caactactag gaccaatgagcagactactg aatttttgtc 30336 cactgtcgag agccacacca cagctacctc cagtgccttctctagcaccg ccaatctctc 30396 ctcgctttcc tctacaccaa tcagtcccgc tactactcccaccccagctc ttctccccac 30456 tcccctgaag caaactgagg acagcggcat gcaatggcagatcaccctgc tcattgtgat 30516 cgggttggtc atcctggccg tgttgctcta ctacatcttctgccgccgca ttcccaacgc 30576 gcaccgcaaa ccggcctaca agcccatcgt tatcgggcagccggagccgc ttcaggtgga 30636 agggggtcta aggaatcttc tcttctcttt tacagtatggtgattgaact atgattccta 30696 gacaattctt gatcactatt cttatctgcc tcctccaagtctgtgccacc ctcgctctgg 30756 tggccaacgc cagtccagac tgtattgggc ccttcgcctcctacgtgctc tttgccttca 30816 tcacctgcat ctgctgctgt agcatagtct gcctgcttatcaccttcttc cagttcattg 30876 actggatctt tgtgcgcatc gcctacctgc gccaccacccccagtaccgc gaccagcgag 30936 tggcgcggct gctcaggctc ctctgataag catgcgggctctgctacttc tcgcgcttct 30996 gctgttagtg ctcccccgcc ccgtcgaccc ccggtcccccactcagtccc ccgaagaggt 31056 ccgcaaatgc aaattccaag aaccctggaa attcctcaaatgctaccgcc aaaaatcaga 31116 catgcttccc agctggatca tgatcattgg gatcgtgaacattctggcct gcaccctcat 31176 ctcctttgtg atttacccct gctttgactt tggttggaactcgccagagg cgctctatct 31236 cccgcctgaa cctgacacac caccacagca acctcaggcacacgcactac caccaccaca 31296 gcctaggcca caatacatgc ccatattaga ctatgaggccgagccacagc gacccatgct 31356 ccccgctatt agttacttca atctaaccgg cggagatgactgacccactg gccaacaaca 31416 acgtcaacga ccttctcctg gacatggacg gccgcgcctcggagcagcga ctcgcccaac 31476 ttcgcattcg ccagcagcag gagagagccg tcaaggagctgcaggacggc atagccatcc 31536 accagtgcaa gaaaggcatc ttctgcctgg tgaaacaggccaagatctcc tacgaggtca 31596 ccccgaccga ccatcgcctc tcctacgagc tcctgcagcagcgccagaag ttcacctgcc 31656 tggtcggagt caaccccatc gtcatcaccc agcagtcgggcgataccaag gggtgcatcc 31716 actgctcctg cgactccccc gactgcgtcc acactctgatcaagaccctc tgcggcctcc 31776 gcgacctcct ccccatgaac taatcacccc cttatccagtgaaataaata tcatattgat 31836 gatgatttaa ataaaaaata atcatttgat ttgaaataaagatacaatca tattgatgat 31896 ttgagtttta aaaaataaag aatcacttac ttgaaatctgataccaggtc tctgtccatg 31956 ttttctgcca acaccacctc actcccctct tcccagctctggtactgcag accccggcgg 32016 gctgcaaact tcctccacac gctgaagggg atgtcaaattcctcctgtcc ctcaatcttc 32076 attttatctt ctatcag atg tcc aaa aag cgc gtccgg gtg gat gat gac 32126 Met Ser Lys Lys Arg Val Arg Val Asp Asp Asp1465 1470 ttc gac ccc gtc tac ccc tac gat gca gac aac gca ccg acc gtg32171 Phe Asp Pro Val Tyr Pro Tyr Asp Ala Asp Asn Ala Pro Thr Val 14751480 1485 ccc ttc atc aac ccc ccc ttc gtc tct tca gat gga ttc caa gag32216 Pro Phe Ile Asn Pro Pro Phe Val Ser Ser Asp Gly Phe Gln Glu 14901495 1500 aag ccc ctg ggg gtg ctg tcc ctg cga ctg gct gac ccc gtc acc32261 Lys Pro Leu Gly Val Leu Ser Leu Arg Leu Ala Asp Pro Val Thr 15051510 1515 acc aag aac ggg gaa atc acc ctc aag ctg gga gag ggg gtg gac32306 Thr Lys Asn Gly Glu Ile Thr Leu Lys Leu Gly Glu Gly Val Asp 15201525 1530 ctc gac tcc tcg gga aaa ctc atc tcc aac acg gcc acc aag gcc32351 Leu Asp Ser Ser Gly Lys Leu Ile Ser Asn Thr Ala Thr Lys Ala 15351540 1545 gcc gcc cct ctc agt ttt tcc aac aac acc att tcc ctt aac atg32396 Ala Ala Pro Leu Ser Phe Ser Asn Asn Thr Ile Ser Leu Asn Met 15501555 1560 gat acc cct ctt tat acc aaa gat gga aaa tta tcc tta caa gtt32441 Asp Thr Pro Leu Tyr Thr Lys Asp Gly Lys Leu Ser Leu Gln Val 15651570 1575 tct cca ccg tta aac ata tta aaa tca acc att ctg aac aca tta32486 Ser Pro Pro Leu Asn Ile Leu Lys Ser Thr Ile Leu Asn Thr Leu 15801585 1590 gct gta gct tat gga tca ggt tta gga ctg agt ggt ggc act gct32531 Ala Val Ala Tyr Gly Ser Gly Leu Gly Leu Ser Gly Gly Thr Ala 15951600 1605 ctt gca gta cag ttg gcc tct cca ctc act ttt gat gaa aaa gga32576 Leu Ala Val Gln Leu Ala Ser Pro Leu Thr Phe Asp Glu Lys Gly 16101615 1620 aat att aaa att aac cta gcc agt ggt cca tta aca gtt gat gca32621 Asn Ile Lys Ile Asn Leu Ala Ser Gly Pro Leu Thr Val Asp Ala 16251630 1635 agt cga ctt agt atc aac tgc aaa aga ggg gtc act gtc act acc32666 Ser Arg Leu Ser Ile Asn Cys Lys Arg Gly Val Thr Val Thr Thr 16401645 1650 tca gga gat gca att gaa agc aac ata agc tgg cct aaa ggt ata32711 Ser Gly Asp Ala Ile Glu Ser Asn Ile Ser Trp Pro Lys Gly Ile 16551660 1665 aga ttt gaa ggt aat ggc ata gct gca aac att ggc aga gga ttg32756 Arg Phe Glu Gly Asn Gly Ile Ala Ala Asn Ile Gly Arg Gly Leu 16701675 1680 gaa ttt gga acc act agt aca gag act gat gtc aca gat gca tac32801 Glu Phe Gly Thr Thr Ser Thr Glu Thr Asp Val Thr Asp Ala Tyr 16851690 1695 cca att caa gtt aaa ttg ggt act ggc ctt acc ttt gac agt aca32846 Pro Ile Gln Val Lys Leu Gly Thr Gly Leu Thr Phe Asp Ser Thr 17001705 1710 ggc gcc att gtt gct tgg aac aaa gag gat gat aaa ctt aca tta32891 Gly Ala Ile Val Ala Trp Asn Lys Glu Asp Asp Lys Leu Thr Leu 17151720 1725 tgg acc aca gcc gac ccc tcg cca aat tgc aaa ata tac tct gaa32936 Trp Thr Thr Ala Asp Pro Ser Pro Asn Cys Lys Ile Tyr Ser Glu 17301735 1740 aaa gat gcc aaa ctc aca ctt tgc ttg aca aag tgt gga agt caa32981 Lys Asp Ala Lys Leu Thr Leu Cys Leu Thr Lys Cys Gly Ser Gln 17451750 1755 att ctg ggt act gtg act gta ttg gca gtg aat aat gga agt ctc33026 Ile Leu Gly Thr Val Thr Val Leu Ala Val Asn Asn Gly Ser Leu 17601765 1770 aac cca atc aca aac aca gta agc act gca ctc gtc tcc ctc aag33071 Asn Pro Ile Thr Asn Thr Val Ser Thr Ala Leu Val Ser Leu Lys 17751780 1785 ttt gat gca agt gga gtt ttg cta agc agc tcc aca tta gac aaa33116 Phe Asp Ala Ser Gly Val Leu Leu Ser Ser Ser Thr Leu Asp Lys 17901795 1800 gaa tat tgg aac ttc aga aag gga gat gtt aca cct gct gag ccc33161 Glu Tyr Trp Asn Phe Arg Lys Gly Asp Val Thr Pro Ala Glu Pro 18051810 1815 tat act aat gct ata ggt ttt atg cct aac ata aag gcc tat cct33206 Tyr Thr Asn Ala Ile Gly Phe Met Pro Asn Ile Lys Ala Tyr Pro 18201825 1830 aaa aac aca tct gca gct tca aaa agc cat att gtc agt caa gtt33251 Lys Asn Thr Ser Ala Ala Ser Lys Ser His Ile Val Ser Gln Val 18351840 1845 tat ctc aat ggg gat gag gcc aaa cca ctg atg ctg att att act33296 Tyr Leu Asn Gly Asp Glu Ala Lys Pro Leu Met Leu Ile Ile Thr 18501855 1860 ttt aat gaa act gag gat gca act tgc acc tac agt atc act ttt33341 Phe Asn Glu Thr Glu Asp Ala Thr Cys Thr Tyr Ser Ile Thr Phe 18651870 1875 caa tgg aaa tgg gat agt act aag tac aca ggt gaa aca ctt gct33386 Gln Trp Lys Trp Asp Ser Thr Lys Tyr Thr Gly Glu Thr Leu Ala 18801885 1890 acc agc tcc ttc acc ttc tcc tac atc gcc caa gaa tga acactgtatc33435 Thr Ser Ser Phe Thr Phe Ser Tyr Ile Ala Gln Glu 1895 1900 1905ccaccctgca tgccaaccct tcccacccca ctctgtctat ggaaaaaact ctgaagcaca 33495aaataaaata aagttcaagt gttttattga ttcaacagtt ttacaggatt cgagcagtta 33555tttttcctcc accctcccag gacatggaat acaccaccct ctccccccgc acagccttga 33615acatctgaat gccattggtg atggacatgc ttttggtctc cacgttccac acagtttcag 33675agcgagccag tctcgggtcg gtcagggaga tgaaaccctc cgggcactcc cgcatctgca 33735cctcacagct caacagctga ggattgtcct cggtggtcgg gatcacggtt atctggaaga 33795agcagaagag cggcggtggg aatcatagtc cgcgaacggg atcggccggt ggtgtcgcat 33855caggccccgc agcagtcgct gccgccgccg ctccgtcaag ctgctgctca gggggtccgg 33915gtccagggac tccctcagca tgatgcccac ggccctcagc atcagtcgtc tggtgcggcg 33975ggcgcagcag cgcatgcgga tctcgctcag gtcgctgcag tacgtgcaac acaggaccac 34035caggttgttc aacagtccat agttcaacac gctccagccg aaactcatcg cgggaaggat 34095gctacccacg tggccgtcgt accagatcct caggtaaatc aagtggcgct ccctccagaa 34155cacgctgccc acgtacatga tctccttggg catgtggcgg ttcaccacct cccggtacca 34215catcaccctc tggttgaaca tgcagccccg gatgatcctg cggaaccaca gggccagcac 34275cgccccgccc gccatgcagc gaagagaccc cgggtcccgg caatggcaat ggaggaccca 34335ccgctcgtac ccgtggatca tctgggagct gaacaagtct atgttggcac agcacaggca 34395tatgctcatg catctcttca gcactctcag ctcctcgggg gtcaaaacca tatcccaggg 34455cacggggaac tcttgcagga cagcgaaccc cgcagaacag ggcaatcctc gcacataact 34515tacattgtgc atggacaggg tatcgcaatc aggcagcacc gggtgatcct ccaccagaga 34575agcgcgggtc tcggtctcct cacagcgtgg taagggggcc ggccgatacg ggtgatggcg 34635ggacgcggct gatcgtgttc gcgaccgtgt catgatgcag ttgctttcgg acattttcgt 34695acttgctgta gcagaacctg gtccgggcgc tgcacaccga tcgccggcgg cggtcccggc 34755gcttggaacg ctcggtgttg aaattgtaaa acagccactc tctcagaccg tgcagcagat 34815ctagggcctc aggagtgatg aagatcccat catgcctgat agctctgatc acatcgacca 34875ccgtggaatg ggccagaccc agccagatga tgcaattttg ttgggtttcg gtgacggcgg 34935gggagggaag aacaggaaga accatgatta acttttaatc caaacggtct cggagcactt 34995caaaatgaag gtcgcggaga tggcacctct cgcccccgct gtgttggtgg aaaataacag 35055ccaggtcaaa ggtgatacgg ttctcgagat gttccacggt ggcttccagc aaagcctcca 35115cgcgcacatc cagaaacaag acaatagcga aagcgggagg gttctctaat tcctcaatca 35175tcatgttaca ctcctgcacc atccccagat aattttcatt tttccagcct tgaatgattc 35235gaactagttc ctgaggtaaa tccaagccag ccatgataaa gagctcgcgc agagcgccct 35295ccaccggcat tcttaagcac accctcataa ttccaagata ttctgctcct ggttcacctg 35355cagcagattg acaagcggaa tatcaaaatc tctgccgcga tccctaagct cctccctcag 35415caataactgt aagtactctt tcatatcctc tccgaaattt ttagccatag gaccaccagg 35475aataagatta gggcaagcca cagtacagat aaaccgaagt cctccccagt gagcattgcc 35535aaatgcaaga ctgctataag catgctggct agacccggtg atatcttcca gataactgga 35595cagaaaatca cccaggcaat ttttaagaaa atcaacaaaa gaaaaatcct ccaggtgcac 35655gtttagagcc tcgggaacaa cgatgaagta aatgcaagcg gtgcgttcca gcatggttag 35715ttagctgatc tgtaaaaaac aaaaaataaa acattaaacc atgctagcct ggcgaacagg 35775tgggtaaatc gttctctcca gcaccaggca ggccacgggg tctccggcgc gaccctcgta 35835aaaattgtcg ctatgattga aaaccatcac agagagacgt tcccggtggc cggcgtgaat 35895gattcgacaa gatgaataca cccccggaac attggcgtcc gcgagtgaaa aaaagcgccc 35955gaggaagcaa taaggcacta caatgctcag tctcaagtcc agcaaagcga tgccatgcgg 36015atgaagcaca aaatcctcag gtgcgtacaa aatgtaatta ctcccctcct gcacaggcag 36075cgaagccccc gatccctcca gatacacata caaagcctca gcgtccatag cttaccgagc 36135agcagcacac aacaggcgca agagtcagag aaaggctgag ctctaacctg tccacccgct 36195ctctgctcaa tatatagccc agatctacac tgacgtaaag gccaaagtct aaaaataccc 36255gccaaataat cacacacgcc cagcacacgc ccagaaaccg gtgacacact caaaaaaata 36315cgcgcacttc ctcaaacgcc caaactgccg tcatttccgg gttcccacgc tacgtcatcg 36375gaattcgact ttcaaattcc gtcgaccgtt aaaaacgtca cccgccccgc ccctaacggt 36435cgcccgtctc tcggccaatc accttcctcc ctccccaaat tcaaacagct catttgcata 36495ttaacgcgca ccaaaagttt gaggtatatt attgatgatg 36535 10 531 PRT chimpanzeeadenovirus serotype Pan7 10 Met Met Arg Arg Val Tyr Pro Glu Gly Pro ProPro Ser Tyr Glu Ser 1 5 10 15 Val Met Gln Gln Ala Val Ala Ala Ala MetGln Pro Pro Leu Glu Ala 20 25 30 Pro Tyr Val Pro Pro Arg Tyr Leu Ala ProThr Glu Gly Arg Asn Ser 35 40 45 Ile Arg Tyr Ser Glu Leu Ala Pro Leu TyrAsp Thr Thr Arg Leu Tyr 50 55 60 Leu Val Asp Asn Lys Ser Ala Asp Ile AlaSer Leu Asn Tyr Gln Asn 65 70 75 80 Asp His Ser Asn Phe Leu Thr Thr ValVal Gln Asn Asn Asp Phe Thr 85 90 95 Pro Thr Glu Ala Ser Thr Gln Thr IleAsn Phe Asp Glu Arg Ser Arg 100 105 110 Trp Gly Gly Gln Leu Lys Thr IleMet His Thr Asn Met Pro Asn Val 115 120 125 Asn Glu Phe Met Tyr Ser AsnLys Phe Lys Ala Arg Val Met Val Ser 130 135 140 Arg Lys Thr Pro Asn GlyVal Ala Val Asp Glu Asn Tyr Asp Gly Ser 145 150 155 160 Gln Asp Glu LeuThr Tyr Glu Trp Val Glu Phe Glu Leu Pro Glu Gly 165 170 175 Asn Phe SerVal Thr Met Thr Ile Asp Leu Met Asn Asn Ala Ile Ile 180 185 190 Asp AsnTyr Leu Ala Val Gly Arg Gln Asn Gly Val Leu Glu Ser Asp 195 200 205 IleGly Val Lys Phe Asp Thr Arg Asn Phe Arg Leu Gly Trp Asp Pro 210 215 220Val Thr Glu Leu Val Met Pro Gly Val Tyr Thr Asn Glu Ala Phe His 225 230235 240 Pro Asp Ile Val Leu Leu Pro Gly Cys Gly Val Asp Phe Thr Glu Ser245 250 255 Arg Leu Ser Asn Leu Leu Gly Ile Arg Lys Arg Gln Pro Phe GlnGlu 260 265 270 Gly Phe Gln Ile Leu Tyr Glu Asp Leu Glu Gly Gly Asn IlePro Ala 275 280 285 Leu Leu Asp Val Glu Ala Tyr Glu Lys Ser Lys Glu GluAla Ala Ala 290 295 300 Ala Ala Thr Ala Ala Val Ala Thr Ala Ser Thr GluVal Arg Gly Asp 305 310 315 320 Asn Phe Ala Ser Ala Ala Ala Val Ala GluAla Ala Glu Thr Glu Ser 325 330 335 Lys Ile Val Ile Gln Pro Val Glu LysAsp Ser Lys Asp Arg Ser Tyr 340 345 350 Asn Val Leu Ala Asp Lys Lys AsnThr Ala Tyr Arg Ser Trp Tyr Leu 355 360 365 Ala Tyr Asn Tyr Gly Asp ProGlu Lys Gly Val Arg Ser Trp Thr Leu 370 375 380 Leu Thr Thr Ser Asp ValThr Cys Gly Val Glu Gln Val Tyr Trp Ser 385 390 395 400 Leu Pro Asp MetMet Gln Asp Pro Val Thr Phe Arg Ser Thr Arg Gln 405 410 415 Val Ser AsnTyr Pro Val Val Gly Ala Glu Leu Leu Pro Val Tyr Ser 420 425 430 Lys SerPhe Phe Asn Glu Gln Ala Val Tyr Ser Gln Gln Leu Arg Ala 435 440 445 PheThr Ser Leu Thr His Val Phe Asn Arg Phe Pro Glu Asn Gln Ile 450 455 460Leu Val Arg Pro Pro Ala Pro Thr Ile Thr Thr Val Ser Glu Asn Val 465 470475 480 Pro Ala Leu Thr Asp His Gly Thr Leu Pro Leu Arg Ser Ser Ile Arg485 490 495 Gly Val Gln Arg Val Thr Val Thr Asp Ala Arg Arg Arg Thr CysPro 500 505 510 Tyr Val Tyr Lys Ala Leu Gly Val Val Ala Pro Arg Val LeuSer Ser 515 520 525 Arg Thr Phe 530 11 932 PRT chimpanzee adenovirusserotype Pan7 11 Met Ala Thr Pro Ser Met Leu Pro Gln Trp Ala Tyr Met HisIle Ala 1 5 10 15 Gly Gln Asp Ala Ser Glu Tyr Leu Ser Pro Gly Leu ValGln Phe Ala 20 25 30 Arg Ala Thr Asp Thr Tyr Phe Ser Leu Gly Asn Lys PheArg Asn Pro 35 40 45 Thr Val Ala Pro Thr His Asp Val Thr Thr Asp Arg SerGln Arg Leu 50 55 60 Thr Leu Arg Phe Val Pro Val Asp Arg Glu Asp Asn ThrTyr Ser Tyr 65 70 75 80 Lys Val Arg Tyr Thr Leu Ala Val Gly Asp Asn ArgVal Leu Asp Met 85 90 95 Ala Ser Thr Tyr Phe Asp Ile Arg Gly Val Leu AspArg Gly Pro Ser 100 105 110 Phe Lys Pro Tyr Ser Gly Thr Ala Tyr Asn SerLeu Ala Pro Lys Gly 115 120 125 Ala Pro Asn Thr Cys Gln Trp Thr Tyr LysAla Gly Asp Thr Asp Thr 130 135 140 Glu Lys Thr Tyr Thr Tyr Gly Asn AlaPro Val Gln Gly Ile Ser Ile 145 150 155 160 Thr Lys Asp Gly Ile Gln LeuGly Thr Asp Ser Asp Gly Gln Ala Ile 165 170 175 Tyr Ala Asp Glu Thr TyrGln Pro Glu Pro Gln Val Gly Asp Ala Glu 180 185 190 Trp His Asp Ile ThrGly Thr Asp Glu Lys Tyr Gly Gly Arg Ala Leu 195 200 205 Lys Pro Asp ThrLys Met Lys Pro Cys Tyr Gly Ser Phe Ala Lys Pro 210 215 220 Thr Asn LysGlu Gly Gly Gln Ala Asn Val Lys Thr Glu Thr Gly Gly 225 230 235 240 ThrLys Glu Tyr Asp Ile Asp Met Ala Phe Phe Asp Asn Arg Ser Ala 245 250 255Ala Ala Ala Gly Leu Ala Pro Glu Ile Val Leu Tyr Thr Glu Asn Val 260 265270 Asp Leu Glu Thr Pro Asp Thr His Ile Val Tyr Lys Ala Gly Thr Asp 275280 285 Asp Ser Ser Ser Ser Ile Asn Leu Gly Gln Gln Ser Met Pro Asn Arg290 295 300 Pro Asn Tyr Ile Gly Phe Arg Asp Asn Phe Ile Gly Leu Met TyrTyr 305 310 315 320 Asn Ser Thr Gly Asn Met Gly Val Leu Ala Gly Gln AlaSer Gln Leu 325 330 335 Asn Ala Val Val Asp Leu Gln Asp Arg Asn Thr GluLeu Ser Tyr Gln 340 345 350 Leu Leu Leu Asp Ser Leu Gly Asp Arg Thr ArgTyr Phe Ser Met Trp 355 360 365 Asn Gln Ala Val Asp Ser Tyr Asp Pro AspVal Arg Ile Ile Glu Asn 370 375 380 His Gly Val Glu Asp Glu Leu Pro AsnTyr Cys Phe Pro Leu Asp Ala 385 390 395 400 Val Gly Arg Thr Asp Thr TyrGln Gly Ile Lys Ala Asn Gly Asp Asn 405 410 415 Gln Thr Thr Trp Thr LysAsp Asp Thr Val Asn Asp Ala Asn Glu Leu 420 425 430 Gly Lys Gly Asn ProPhe Ala Met Glu Ile Asn Ile Gln Ala Asn Leu 435 440 445 Trp Arg Asn PheLeu Tyr Ala Asn Val Ala Leu Tyr Leu Pro Asp Ser 450 455 460 Tyr Lys TyrThr Pro Ala Asn Ile Thr Leu Pro Thr Asn Thr Asn Thr 465 470 475 480 TyrAsp Tyr Met Asn Gly Arg Val Val Ala Pro Ser Leu Val Asp Ala 485 490 495Tyr Ile Asn Ile Gly Ala Arg Trp Ser Leu Asp Pro Met Asp Asn Val 500 505510 Asn Pro Phe Asn His His Arg Asn Ala Gly Leu Arg Tyr Arg Ser Met 515520 525 Leu Leu Gly Asn Gly Arg Tyr Val Pro Phe His Ile Gln Val Pro Gln530 535 540 Lys Phe Phe Ala Ile Lys Ser Leu Leu Leu Leu Pro Gly Ser TyrThr 545 550 555 560 Tyr Glu Trp Asn Phe Arg Lys Asp Val Asn Met Ile LeuGln Ser Ser 565 570 575 Leu Gly Asn Asp Leu Arg Thr Asp Gly Ala Ser IleAla Phe Thr Ser 580 585 590 Ile Asn Leu Tyr Ala Thr Phe Phe Pro Met AlaHis Asn Thr Ala Ser 595 600 605 Thr Leu Glu Ala Met Leu Arg Asn Asp ThrAsn Asp Gln Ser Phe Asn 610 615 620 Asp Tyr Leu Ser Ala Ala Asn Met LeuTyr Pro Ile Pro Ala Asn Ala 625 630 635 640 Thr Asn Val Pro Ile Ser IlePro Ser Arg Asn Trp Ala Ala Phe Arg 645 650 655 Gly Trp Ser Phe Thr ArgLeu Lys Thr Arg Glu Thr Pro Ser Leu Gly 660 665 670 Ser Gly Phe Asp ProTyr Phe Val Tyr Ser Gly Ser Ile Pro Tyr Leu 675 680 685 Asp Gly Thr PheTyr Leu Asn His Thr Phe Lys Lys Val Ser Ile Thr 690 695 700 Phe Asp SerSer Val Ser Trp Pro Gly Asn Asp Arg Leu Leu Thr Pro 705 710 715 720 AsnGlu Phe Glu Ile Lys Arg Thr Val Asp Gly Glu Gly Tyr Asn Val 725 730 735Ala Gln Cys Asn Met Thr Lys Asp Trp Phe Leu Val Gln Met Leu Ala 740 745750 His Tyr Asn Ile Gly Tyr Gln Gly Phe Tyr Val Pro Glu Gly Tyr Lys 755760 765 Asp Arg Met Tyr Ser Phe Phe Arg Asn Phe Gln Pro Met Ser Arg Gln770 775 780 Val Val Asp Glu Val Asn Tyr Lys Asp Tyr Gln Ala Val Thr LeuAla 785 790 795 800 Tyr Gln His Asn Asn Ser Gly Phe Val Gly Tyr Leu AlaPro Thr Met 805 810 815 Arg Gln Gly Gln Pro Tyr Pro Ala Asn Tyr Pro TyrPro Leu Ile Gly 820 825 830 Lys Ser Ala Val Ala Ser Val Thr Gln Lys LysPhe Leu Cys Asp Arg 835 840 845 Val Met Trp Arg Ile Pro Phe Ser Ser AsnPhe Met Ser Met Gly Ala 850 855 860 Leu Thr Asp Leu Gly Gln Asn Met LeuTyr Ala Asn Ser Ala His Ala 865 870 875 880 Leu Asp Met Asn Phe Glu ValAsp Pro Met Asp Glu Ser Thr Leu Leu 885 890 895 Tyr Val Val Phe Glu ValPhe Asp Val Val Arg Val His Gln Pro His 900 905 910 Arg Gly Val Ile GluAla Val Tyr Leu Arg Thr Pro Phe Ser Ala Gly 915 920 925 Asn Ala Thr Thr930 12 443 PRT chimpanzee adenovirus serotype Pan7 12 Met Ser Lys LysArg Val Arg Val Asp Asp Asp Phe Asp Pro Val Tyr 1 5 10 15 Pro Tyr AspAla Asp Asn Ala Pro Thr Val Pro Phe Ile Asn Pro Pro 20 25 30 Phe Val SerSer Asp Gly Phe Gln Glu Lys Pro Leu Gly Val Leu Ser 35 40 45 Leu Arg LeuAla Asp Pro Val Thr Thr Lys Asn Gly Glu Ile Thr Leu 50 55 60 Lys Leu GlyGlu Gly Val Asp Leu Asp Ser Ser Gly Lys Leu Ile Ser 65 70 75 80 Asn ThrAla Thr Lys Ala Ala Ala Pro Leu Ser Phe Ser Asn Asn Thr 85 90 95 Ile SerLeu Asn Met Asp Thr Pro Leu Tyr Thr Lys Asp Gly Lys Leu 100 105 110 SerLeu Gln Val Ser Pro Pro Leu Asn Ile Leu Lys Ser Thr Ile Leu 115 120 125Asn Thr Leu Ala Val Ala Tyr Gly Ser Gly Leu Gly Leu Ser Gly Gly 130 135140 Thr Ala Leu Ala Val Gln Leu Ala Ser Pro Leu Thr Phe Asp Glu Lys 145150 155 160 Gly Asn Ile Lys Ile Asn Leu Ala Ser Gly Pro Leu Thr Val AspAla 165 170 175 Ser Arg Leu Ser Ile Asn Cys Lys Arg Gly Val Thr Val ThrThr Ser 180 185 190 Gly Asp Ala Ile Glu Ser Asn Ile Ser Trp Pro Lys GlyIle Arg Phe 195 200 205 Glu Gly Asn Gly Ile Ala Ala Asn Ile Gly Arg GlyLeu Glu Phe Gly 210 215 220 Thr Thr Ser Thr Glu Thr Asp Val Thr Asp AlaTyr Pro Ile Gln Val 225 230 235 240 Lys Leu Gly Thr Gly Leu Thr Phe AspSer Thr Gly Ala Ile Val Ala 245 250 255 Trp Asn Lys Glu Asp Asp Lys LeuThr Leu Trp Thr Thr Ala Asp Pro 260 265 270 Ser Pro Asn Cys Lys Ile TyrSer Glu Lys Asp Ala Lys Leu Thr Leu 275 280 285 Cys Leu Thr Lys Cys GlySer Gln Ile Leu Gly Thr Val Thr Val Leu 290 295 300 Ala Val Asn Asn GlySer Leu Asn Pro Ile Thr Asn Thr Val Ser Thr 305 310 315 320 Ala Leu ValSer Leu Lys Phe Asp Ala Ser Gly Val Leu Leu Ser Ser 325 330 335 Ser ThrLeu Asp Lys Glu Tyr Trp Asn Phe Arg Lys Gly Asp Val Thr 340 345 350 ProAla Glu Pro Tyr Thr Asn Ala Ile Gly Phe Met Pro Asn Ile Lys 355 360 365Ala Tyr Pro Lys Asn Thr Ser Ala Ala Ser Lys Ser His Ile Val Ser 370 375380 Gln Val Tyr Leu Asn Gly Asp Glu Ala Lys Pro Leu Met Leu Ile Ile 385390 395 400 Thr Phe Asn Glu Thr Glu Asp Ala Thr Cys Thr Tyr Ser Ile ThrPhe 405 410 415 Gln Trp Lys Trp Asp Ser Thr Lys Tyr Thr Gly Glu Thr LeuAla Thr 420 425 430 Ser Ser Phe Thr Phe Ser Tyr Ile Ala Gln Glu 435 44013 338 PRT simian serotype C1 13 Ala Pro Lys Gly Ala Pro Asn Thr Ser GlnTrp Leu Asp Lys Gly Val 1 5 10 15 Thr Thr Thr Asp Asn Asn Thr Glu AsnGly Asp Glu Glu Asp Glu Val 20 25 30 Ala Glu Glu Gly Glu Glu Glu Lys GlnAla Thr Tyr Thr Phe Gly Asn 35 40 45 Ala Pro Val Lys Ala Glu Ala Glu IleThr Lys Glu Gly Leu Pro Ile 50 55 60 Gly Leu Glu Val Pro Ser Glu Gly AspPro Lys Pro Ile Tyr Ala Asp 65 70 75 80 Lys Leu Tyr Gln Pro Glu Pro GlnVal Gly Glu Glu Ser Trp Thr Asp 85 90 95 Thr Asp Gly Thr Asp Glu Lys TyrGly Gly Arg Ala Leu Lys Pro Glu 100 105 110 Thr Lys Met Lys Pro Cys TyrGly Ser Phe Ala Lys Pro Thr Asn Val 115 120 125 Lys Gly Gly Gln Ala LysVal Lys Lys Val Glu Glu Gly Lys Val Glu 130 135 140 Tyr Asp Ile Asp MetAsn Phe Phe Asp Leu Arg Ser Gln Lys Thr Gly 145 150 155 160 Leu Lys ProLys Ile Val Met Tyr Ala Glu Asn Val Asp Leu Glu Thr 165 170 175 Pro AspThr His Val Val Tyr Lys Pro Gly Ala Ser Asp Ala Ser Ser 180 185 190 HisAla Asn Leu Gly Gln Gln Ser Met Pro Asn Arg Pro Asn Tyr Ile 195 200 205Gly Phe Arg Asp Asn Phe Ile Gly Leu Met Tyr Tyr Asn Ser Thr Gly 210 215220 Asn Met Gly Val Leu Ala Gly Gln Ala Ser Gln Leu Asn Ala Val Val 225230 235 240 Asp Leu Gln Asp Arg Asn Thr Glu Leu Ser Tyr Gln Leu Leu LeuAsp 245 250 255 Ser Leu Gly Asp Arg Thr Arg Tyr Phe Ser Met Trp Asn GlnAla Val 260 265 270 Asp Ser Tyr Asp Pro Asp Val Arg Val Ile Glu Asn HisGly Val Glu 275 280 285 Asp Glu Leu Pro Asn Tyr Cys Phe Pro Leu Asp GlyVal Gly Pro Arg 290 295 300 Thr Asp Ser Tyr Lys Gly Ile Glu Thr Asn GlyAsp Glu Asn Thr Thr 305 310 315 320 Trp Lys Asp Leu Asp Pro Asn Gly IleSer Glu Leu Ala Lys Gly Asn 325 330 335 Pro Phe 14 315 PRT chimpanzeeadenovirus Pan-9 14 Ala Pro Lys Gly Ala Pro Asn Thr Cys Gln Trp Thr TyrLys Ala Asp 1 5 10 15 Gly Glu Thr Ala Thr Glu Lys Thr Tyr Thr Tyr GlyAsn Ala Pro Val 20 25 30 Gln Gly Ile Asn Ile Thr Lys Asp Gly Ile Gln LeuGly Thr Asp Thr 35 40 45 Asp Asp Gln Pro Ile Tyr Ala Asp Lys Thr Tyr GlnPro Glu Pro Gln 50 55 60 Val Gly Asp Ala Glu Trp His Asp Ile Thr Gly ThrAsp Glu Lys Tyr 65 70 75 80 Gly Gly Arg Ala Leu Lys Pro Asp Thr Lys MetLys Pro Cys Tyr Gly 85 90 95 Ser Phe Ala Lys Pro Thr Asn Lys Glu Gly GlyGln Ala Asn Val Lys 100 105 110 Thr Gly Thr Gly Thr Thr Lys Glu Tyr AspIle Asp Met Ala Phe Phe 115 120 125 Asp Asn Arg Ser Ala Ala Ala Ala GlyLeu Ala Pro Glu Ile Val Leu 130 135 140 Tyr Thr Glu Asn Val Asp Leu GluThr Pro Asp Thr His Ile Val Tyr 145 150 155 160 Lys Ala Gly Thr Asp AspSer Ser Ser Ser Ile Asn Leu Gly Gln Gln 165 170 175 Ala Met Pro Asn ArgPro Asn Tyr Ile Gly Phe Arg Asp Asn Phe Ile 180 185 190 Gly Leu Met TyrTyr Asn Ser Thr Gly Asn Met Gly Val Leu Ala Gly 195 200 205 Gln Ala SerGln Leu Asn Ala Val Val Asp Leu Gln Asp Arg Asn Thr 210 215 220 Glu LeuSer Tyr Gln Leu Leu Leu Asp Ser Leu Gly Asp Arg Thr Arg 225 230 235 240Tyr Phe Ser Met Trp Asn Gln Ala Val Asp Ser Tyr Asp Pro Asp Val 245 250255 Arg Ile Ile Glu Asn His Gly Val Glu Asp Glu Leu Pro Asn Tyr Cys 260265 270 Phe Pro Leu Asp Ala Val Gly Arg Thr Asp Thr Tyr Gln Gly Ile Lys275 280 285 Ala Asn Gly Thr Asp Gln Thr Thr Trp Thr Lys Asp Asp Ser ValAsn 290 295 300 Asp Ala Asn Glu Ile Gly Lys Gly Asn Pro Phe 305 310 31515 315 PRT chimpanzee adenovirus Pan-5 15 Ala Pro Lys Gly Ala Pro AsnThr Cys Gln Trp Thr Tyr Lys Ala Asp 1 5 10 15 Gly Asp Thr Gly Thr GluLys Thr Tyr Thr Tyr Gly Asn Ala Pro Val 20 25 30 Gln Gly Ile Ser Ile ThrLys Asp Gly Ile Gln Leu Gly Thr Asp Thr 35 40 45 Asp Asp Gln Pro Ile TyrAla Asp Lys Thr Tyr Gln Pro Glu Pro Gln 50 55 60 Val Gly Asp Ala Glu TrpHis Asp Ile Thr Gly Thr Asp Glu Lys Tyr 65 70 75 80 Gly Gly Arg Ala LeuLys Pro Asp Thr Lys Met Lys Pro Cys Tyr Gly 85 90 95 Ser Phe Ala Lys ProThr Asn Lys Glu Gly Gly Gln Ala Asn Val Lys 100 105 110 Thr Glu Thr GlyGly Thr Lys Glu Tyr Asp Ile Asp Met Ala Phe Phe 115 120 125 Asp Asn ArgSer Ala Ala Ala Ala Gly Leu Ala Pro Glu Ile Val Leu 130 135 140 Tyr ThrGlu Asn Val Asp Leu Glu Thr Pro Asp Thr His Ile Val Tyr 145 150 155 160Lys Ala Gly Thr Asp Asp Ser Ser Ser Ser Ile Asn Leu Gly Gln Gln 165 170175 Ser Met Pro Asn Arg Pro Asn Tyr Ile Gly Phe Arg Asp Asn Phe Ile 180185 190 Gly Leu Met Tyr Tyr Asn Ser Thr Gly Asn Met Gly Val Leu Ala Gly195 200 205 Gln Ala Ser Gln Leu Asn Ala Val Val Asp Leu Gln Asp Arg AsnThr 210 215 220 Glu Leu Ser Tyr Gln Leu Leu Leu Asp Ser Leu Gly Asp ArgThr Arg 225 230 235 240 Tyr Phe Ser Met Trp Asn Gln Ala Val Asp Ser TyrAsp Pro Asp Val 245 250 255 Arg Ile Ile Glu Asn His Gly Val Glu Asp GluLeu Pro Asn Tyr Cys 260 265 270 Phe Pro Leu Asp Ala Val Gly Arg Thr AspThr Tyr Gln Gly Ile Lys 275 280 285 Ala Asn Gly Ala Asp Gln Thr Thr TrpThr Lys Asp Asp Thr Val Asn 290 295 300 Asp Ala Asn Glu Leu Gly Lys GlyAsn Pro Phe 305 310 315 16 324 PRT chimpanzee adenovirus Pan-6 16 AlaPro Lys Gly Ala Pro Asn Ser Ser Gln Trp Glu Gln Ala Lys Thr 1 5 10 15Gly Asn Gly Gly Thr Met Glu Thr His Thr Tyr Gly Val Ala Pro Met 20 25 30Gly Gly Glu Asn Ile Thr Lys Asp Gly Leu Gln Ile Gly Thr Asp Val 35 40 45Thr Ala Asn Gln Asn Lys Pro Ile Tyr Ala Asp Lys Thr Phe Gln Pro 50 55 60Glu Pro Gln Val Gly Glu Glu Asn Trp Gln Glu Thr Glu Asn Phe Tyr 65 70 7580 Gly Gly Arg Ala Leu Lys Lys Asp Thr Lys Met Lys Pro Cys Tyr Gly 85 9095 Ser Tyr Ala Arg Pro Thr Asn Glu Lys Gly Gly Gln Ala Lys Leu Lys 100105 110 Val Gly Asp Asp Gly Val Pro Thr Lys Glu Phe Asp Ile Asp Leu Ala115 120 125 Phe Phe Asp Thr Pro Gly Gly Thr Val Asn Gly Gln Asp Glu TyrLys 130 135 140 Ala Asp Ile Val Met Tyr Thr Glu Asn Thr Tyr Leu Glu ThrPro Asp 145 150 155 160 Thr His Val Val Tyr Lys Pro Gly Lys Asp Asp AlaSer Ser Glu Ile 165 170 175 Asn Leu Val Gln Gln Ser Met Pro Asn Arg ProAsn Tyr Ile Gly Phe 180 185 190 Arg Asp Asn Phe Ile Gly Leu Met Tyr TyrAsn Ser Thr Gly Asn Met 195 200 205 Gly Val Leu Ala Gly Gln Ala Ser GlnLeu Asn Ala Val Val Asp Leu 210 215 220 Gln Asp Arg Asn Thr Glu Leu SerTyr Gln Leu Leu Leu Asp Ser Leu 225 230 235 240 Gly Asp Arg Thr Arg TyrPhe Ser Met Trp Asn Gln Ala Val Asp Ser 245 250 255 Tyr Asp Pro Asp ValArg Ile Ile Glu Asn His Gly Val Glu Asp Glu 260 265 270 Leu Pro Asn TyrCys Phe Pro Leu Asp Gly Ser Gly Thr Asn Ala Ala 275 280 285 Tyr Gln GlyVal Lys Val Lys Asp Gly Gln Asp Gly Asp Val Glu Ser 290 295 300 Glu TrpGlu Asn Asp Asp Thr Val Ala Ala Arg Asn Gln Leu Cys Lys 305 310 315 320Gly Asn Ile Phe 17 314 PRT chimpanzee adenovirus Pan-7 17 Ala Pro LysGly Ala Pro Asn Thr Cys Gln Trp Thr Tyr Lys Ala Gly 1 5 10 15 Asp ThrAsp Thr Glu Lys Thr Tyr Thr Tyr Gly Asn Ala Pro Val Gln 20 25 30 Gly IleSer Ile Thr Lys Asp Gly Ile Gln Leu Gly Thr Asp Ser Asp 35 40 45 Gly GlnAla Ile Tyr Ala Asp Glu Thr Tyr Gln Pro Glu Pro Gln Val 50 55 60 Gly AspAla Glu Trp His Asp Ile Thr Gly Thr Asp Glu Lys Tyr Gly 65 70 75 80 GlyArg Ala Leu Lys Pro Asp Thr Lys Met Lys Pro Cys Tyr Gly Ser 85 90 95 PheAla Lys Pro Thr Asn Lys Glu Gly Gly Gln Ala Asn Val Lys Thr 100 105 110Glu Thr Gly Gly Thr Lys Glu Tyr Asp Ile Asp Met Ala Phe Phe Asp 115 120125 Asn Arg Ser Ala Ala Ala Ala Gly Leu Ala Pro Glu Ile Val Leu Tyr 130135 140 Thr Glu Asn Val Asp Leu Glu Thr Pro Asp Thr His Ile Val Tyr Lys145 150 155 160 Ala Gly Thr Asp Asp Ser Ser Ser Ser Ile Asn Leu Gly GlnGln Ser 165 170 175 Met Pro Asn Arg Pro Asn Tyr Ile Gly Phe Arg Asp AsnPhe Ile Gly 180 185 190 Leu Met Tyr Tyr Asn Ser Thr Gly Asn Met Gly ValLeu Ala Gly Gln 195 200 205 Ala Ser Gln Leu Asn Ala Val Val Asp Leu GlnAsp Arg Asn Thr Glu 210 215 220 Leu Ser Tyr Gln Leu Leu Leu Asp Ser LeuGly Asp Arg Thr Arg Tyr 225 230 235 240 Phe Ser Met Trp Asn Gln Ala ValAsp Ser Tyr Asp Pro Asp Val Arg 245 250 255 Ile Ile Glu Asn His Gly ValGlu Asp Glu Leu Pro Asn Tyr Cys Phe 260 265 270 Pro Leu Asp Ala Val GlyArg Thr Asp Thr Tyr Gln Gly Ile Lys Ala 275 280 285 Asn Gly Asp Asn GlnThr Thr Trp Thr Lys Asp Asp Thr Val Asn Asp 290 295 300 Ala Asn Glu LeuGly Lys Gly Asn Pro Phe 305 310 18 179 PRT chimpanzee adenovirus Pan9 18Thr Leu Trp Thr Thr Pro Asp Pro Ser Pro Asn Cys Gln Ile Leu Ala 1 5 1015 Glu Asn Asp Ala Lys Leu Thr Leu Cys Leu Thr Lys Cys Gly Ser Gln 20 2530 Ile Leu Ala Thr Val Ser Val Leu Val Val Gly Ser Gly Asn Leu Asn 35 4045 Pro Ile Thr Gly Thr Val Ser Ser Ala Gln Val Phe Leu Arg Phe Asp 50 5560 Ala Asn Gly Val Leu Leu Thr Glu His Ser Thr Leu Lys Lys Tyr Trp 65 7075 80 Gly Tyr Arg Gln Gly Asp Ser Ile Asp Gly Thr Pro Tyr Thr Asn Ala 8590 95 Val Gly Phe Met Pro Asn Leu Lys Ala Tyr Pro Lys Ser Gln Ser Ser100 105 110 Thr Thr Lys Asn Asn Ile Val Gly Gln Val Tyr Met Asn Gly AspVal 115 120 125 Ser Lys Pro Met Leu Leu Thr Ile Thr Leu Asn Gly Thr AspAsp Ser 130 135 140 Asn Ser Thr Tyr Ser Met Ser Phe Ser Tyr Thr Trp ThrAsn Gly Ser 145 150 155 160 Tyr Val Gly Ala Thr Phe Gly Ala Asn Ser TyrThr Phe Ser Tyr Ile 165 170 175 Ala Gln Glu 19 185 PRT chimpanzeeadenovirus Pan6 19 Thr Leu Trp Thr Thr Pro Asp Pro Ser Pro Asn Cys GlnLeu Leu Ser 1 5 10 15 Asp Arg Asp Ala Lys Phe Thr Leu Cys Leu Thr LysCys Gly Ser Gln 20 25 30 Ile Leu Gly Thr Val Ala Val Ala Ala Val Thr ValGly Ser Ala Leu 35 40 45 Asn Pro Ile Asn Asp Thr Val Lys Ser Ala Ile ValPhe Leu Arg Phe 50 55 60 Asp Ser Asp Gly Val Leu Met Ser Asn Ser Ser MetVal Gly Asp Tyr 65 70 75 80 Trp Asn Phe Arg Glu Gly Gln Thr Thr Gln SerVal Ala Tyr Thr Asn 85 90 95 Ala Val Gly Phe Met Pro Asn Ile Gly Ala TyrPro Lys Thr Gln Ser 100 105 110 Lys Thr Pro Lys Asn Ser Ile Val Ser GlnVal Tyr Leu Thr Gly Glu 115 120 125 Thr Thr Met Pro Met Thr Leu Thr IleThr Phe Asn Gly Thr Asp Glu 130 135 140 Lys Asp Thr Thr Pro Val Ser ThrTyr Ser Met Thr Phe Thr Trp Gln 145 150 155 160 Trp Thr Gly Asp Tyr LysAsp Lys Asn Ile Thr Phe Ala Thr Asn Ser 165 170 175 Phe Ser Phe Ser TyrIle Ala Gln Glu 180 185 20 179 PRT chimpanzee adenovirus Pan7 20 Thr LeuTrp Thr Thr Ala Asp Pro Ser Pro Asn Cys Lys Ile Tyr Ser 1 5 10 15 GluLys Asp Ala Lys Leu Thr Leu Cys Leu Thr Lys Cys Gly Ser Gln 20 25 30 IleLeu Gly Thr Val Thr Val Leu Ala Val Asn Asn Gly Ser Leu Asn 35 40 45 ProIle Thr Asn Thr Val Ser Thr Ala Leu Val Ser Leu Lys Phe Asp 50 55 60 AlaSer Gly Val Leu Leu Ser Ser Ser Thr Leu Asp Lys Glu Tyr Trp 65 70 75 80Asn Phe Arg Lys Gly Asp Val Thr Pro Ala Glu Pro Tyr Thr Asn Ala 85 90 95Ile Gly Phe Met Pro Asn Ile Lys Ala Tyr Pro Lys Asn Thr Ser Ala 100 105110 Ala Ser Lys Ser His Ile Val Ser Gln Val Tyr Leu Asn Gly Asp Glu 115120 125 Ala Lys Pro Leu Met Leu Ile Ile Thr Phe Asn Glu Thr Glu Asp Ala130 135 140 Thr Cys Thr Tyr Ser Ile Thr Phe Gln Trp Lys Trp Asp Ser ThrLys 145 150 155 160 Tyr Thr Gly Glu Thr Leu Ala Thr Ser Ser Phe Thr PheSer Tyr Ile 165 170 175 Ala Gln Glu 21 179 PRT chimpanzee adenovirusPan5 21 Thr Leu Trp Thr Thr Ala Asp Pro Ser Pro Asn Cys His Ile Tyr Ser1 5 10 15 Glu Lys Asp Ala Lys Leu Thr Leu Cys Leu Thr Lys Cys Gly SerGln 20 25 30 Ile Leu Gly Thr Val Ser Leu Ile Ala Val Asp Thr Gly Ser LeuAsn 35 40 45 Pro Ile Thr Gly Thr Val Thr Thr Ala Leu Val Ser Leu Lys PheAsp 50 55 60 Ala Asn Gly Val Leu Gln Ser Ser Ser Thr Leu Asp Ser Asp TyrTrp 65 70 75 80 Asn Phe Arg Gln Gly Asp Val Thr Pro Ala Glu Ala Tyr ThrAsn Ala 85 90 95 Ile Gly Phe Met Pro Asn Leu Lys Ala Tyr Pro Lys Asn ThrSer Gly 100 105 110 Ala Ala Lys Ser His Ile Val Gly Lys Val Tyr Leu HisGly Asp Thr 115 120 125 Gly Lys Pro Leu Asp Leu Ile Ile Thr Phe Asn GluThr Ser Asp Glu 130 135 140 Ser Cys Thr Tyr Cys Ile Asn Phe Gln Trp GlnTrp Gly Ala Asp Gln 145 150 155 160 Tyr Lys Asn Glu Thr Leu Ala Val SerSer Phe Thr Phe Ser Tyr Ile 165 170 175 Ala Lys Glu 22 183 PRT humanadenovirus Ad 2 22 Thr Leu Trp Thr Thr Pro Asp Pro Ser Pro Asn Cys ArgIle His Ser 1 5 10 15 Asp Asn Asp Cys Lys Phe Thr Leu Val Leu Thr LysCys Gly Ser Gln 20 25 30 Val Leu Ala Thr Val Ala Ala Leu Ala Val Ser GlyAsp Leu Ser Ser 35 40 45 Met Thr Gly Thr Val Ala Ser Val Ser Ile Phe LeuArg Phe Asp Gln 50 55 60 Asn Gly Val Leu Met Glu Asn Ser Ser Leu Lys LysHis Tyr Trp Asn 65 70 75 80 Phe Arg Asn Gly Asn Ser Thr Asn Ala Asn ProTyr Thr Asn Ala Val 85 90 95 Gly Phe Met Pro Asn Leu Leu Ala Tyr Pro LysThr Gln Ser Gln Thr 100 105 110 Ala Lys Asn Asn Ile Val Ser Gln Val TyrLeu His Gly Asp Lys Thr 115 120 125 Lys Pro Met Ile Leu Thr Ile Thr LeuAsn Gly Thr Ser Glu Ser Thr 130 135 140 Glu Thr Ser Glu Val Ser Thr TyrSer Met Ser Phe Thr Trp Ser Trp 145 150 155 160 Glu Ser Gly Lys Tyr ThrThr Glu Thr Phe Ala Thr Asn Ser Tyr Thr 165 170 175 Phe Ser Tyr Ile AlaGln Glu 180 23 182 PRT human adenovirus Ad 5 23 Thr Leu Trp Thr Thr ProAla Pro Ser Pro Asn Cys Arg Leu Asn Ala 1 5 10 15 Glu Lys Asp Ala LysLeu Thr Leu Val Leu Thr Lys Cys Gly Ser Gln 20 25 30 Ile Leu Ala Thr ValSer Val Leu Ala Val Lys Gly Ser Leu Ala Pro 35 40 45 Ile Ser Gly Thr ValGln Ser Ala His Leu Ile Ile Arg Phe Asp Glu 50 55 60 Asn Gly Val Leu IleAsn Asn Ser Phe Leu Asp Pro Glu Tyr Trp Asn 65 70 75 80 Phe Arg Asn GlyAsp Leu Thr Glu Gly Thr Ala Tyr Thr Asn Ala Val 85 90 95 Gly Phe Met ProAsn Leu Ser Ala Tyr Pro Lys Ser His Gly Lys Thr 100 105 110 Ala Lys SerAsn Ile Val Ser Gln Val Tyr Leu Asn Gly Asp Lys Thr 115 120 125 Lys ProVal Thr Leu Thr Ile Thr Leu Asn Gly Thr Gln Glu Thr Gly 130 135 140 AspThr Thr Pro Ser Ala Tyr Ser Met Ser Phe Ser Trp Asp Trp Ser 145 150 155160 Gly His Asn Tyr Ile Asn Glu Ile Phe Ala Thr Ser Ser Tyr Thr Glu 165170 175 Ser Tyr Ile Ala Gln Glu 180 24 34264 DNA simian adenovirus SV-1CDS (12454)..(13965) L2 Penton 24 tccttattct ggaaacgtgc caatatgataatgagcgggg aggagcgagg cggggccggg 60 gtgacgtgcg gtgacgtggg gtgacgcggggtggcgcgag ggcggggcgg gagtggggag 120 gcgcttagtt tttacgtatg cggaaggaggttttataccg gaagttgggt aatttgggcg 180 tatacttgta agttttgtgt aatttggcgcgaaaaccggg taatgaggaa gttgaggtta 240 atatgtactt tttatgactg ggcggaatttctgctgatca gcagtgaact ttgggcgctg 300 acggggaggt ttcgctacgt ggcagtaccacgagaaggct caaaggtccc atttattgta 360 ctcctcagcg ttttcgctgg gtatttaaacgctgtcagat catcaagagg ccactcttga 420 gtgccggcga gtagagtttt ctcctccgcgctgccgcgat gaggctggtt cccgagatgt 480 acggtgtttt ctgcagcgag acggcccggaactcagatga gctgcttaat acagatctgc 540 tggatgttcc caactcgcct gtggcttcgcctccgtcgct tcatgatctt ttcgatgtgg 600 aagtggatcc accgcaagat cccaacgaggacgcggtaaa cagtatgttc cctgaatgtc 660 tgtttgaggc ggctgaggag ggttctcacagcagtgaaga gagcagacgg ggagaggaac 720 tggacttgaa atgctacgag gaatgtctgccttctagcga ttctgaaacg gaacagacag 780 ggggagacgg ctgtgagtcg gcaatgaaaaatgaacttgt attagactgt ccagaacatc 840 ctggtcatgg ctgccgtgcc tgtgcttttcatagaaatgc cagcggaaat cctgagactc 900 tatgtgctct gtgttatctg cgccttaccagcgattttgt atacagtaag taaagtgttt 960 tcattggcgt acggtagggg attcgttgaagtgctttgtg acttattatg tgtcattatt 1020 tctaggtgac gtgtccgacg tggaaggggaaggagataga tcaggggctg ctaattctcc 1080 ttgcactttg ggggctgtgg ttccagttggcatttttaaa ccgagtggtg gaggagaacg 1140 agccggagga gaccgagaat ctgagagccggcctggaccc tccagtggaa gactaggtgc 1200 tgaggatgat cctgaagagg ggactagtgggggtgctagg aaaaagcaaa aaactgagcc 1260 tgaacctaga aactttttga atgagttgactgtaagccta atgaatcggc agcgtcctga 1320 gacggtgttt tggactgagt tggaggatgagttcaagaag ggggaattaa acctcttgta 1380 caagtatggg tttgagcagt tgaaaactcactggttggag ccgtgggagg atatggaaat 1440 ggctctagac acctttgcta aagtggctctgcggccggat aaagtttaca ctattcgccg 1500 cactgttaat ataaaaaaga gtgtttatgttatcggccat ggagctctgg tgcaggtgca 1560 gaccccagac cgggtggctt tcaattgcggcatgcagagt ttgggccccg gggtgatagg 1620 tttgaatgga gttacatttc aaaatgtcaggtttactggt gatgatttta atggctctgt 1680 gtttgtgact agcacccagc taaccctccacggtgtttac ttttttaact ttaacaatac 1740 atgtgtggag tcatggggta gggtgtctctgaggggctgc agttttcatg gttgctggaa 1800 ggcggtggtg ggaagaatta aaagtgtcatgtctgtgaag aaatgcatat ttgaacgctg 1860 tgtgatagct ctagcagtag aggggtacggacggatcagg aataacgccg catctgagaa 1920 tggatgtttt cttttgctga aaggtacggccagcgttaag cataatatga tttgcggcag 1980 cggcctgtgc ccctcgcagc tcttaacttgcgcagatgga aactgtcaca ccttgcgcac 2040 cgtgcacata gtgtcccact cgcgccgcacctggccaaca tttgagcaca atatgctcat 2100 gcgttgcgcc gttcacctag gtgctagacgcggcgtgttt atgccttatc aatgtaactt 2160 tagtcatact aagattttgc tggaaactgattccttccct cgagtatgtt tcaatggggt 2220 gtttgacatg tcaatggaac tttttaaagtgataagatat gatgaaacca agtctcgttg 2280 tcgctcatgt gaatgcggag ctaatcatttgaggttgtat cctgtaaccc tgaacgttac 2340 cgaggagctg aggacggacc accacatgctgtcttgcctg cgtaccgact atgaatccag 2400 cgatgaggag tgaggtgagg ggcggagccacaaagggtat aaaggggcat gaggggtggg 2460 cgcggtgttt caaaatgagc gggacgacggacggcaatgc gtttgagggg ggagtgttca 2520 gcccatatct gacatctcgt cttccttcctgggcaggagt tcgtcagaat gtagtgggct 2580 ccaccgtgga cggacggccg gtcgcccctgcaaattccgc caccctcacc tatgccaccg 2640 tgggatcatc gttggacact gccgcggcagctgccgcttc tgctgccgct tctactgctc 2700 gcggcatggc ggctgatttt ggactatataaccaactggc cactgcagct gtggcgtctc 2760 ggtctctggt tcaagaagat gccctgaatgtgatcttgac tcgcctggag atcatgtcac 2820 gtcgcctgga cgaactggct gcgcagatatcccaagctaa ccccgatacc gcttcagaat 2880 cttaaaataa agacaaacaa atttgttgaaaagtaaaatg gctttatttg ttttttttgg 2940 ctcggtaggc tcgggtccac ctgtctcggtcgttaaggac tttgtgtatg ttttccaaaa 3000 cacggtacag atgggcttgg atgttcaagtacatgggcat gaggccatct ttggggtgga 3060 gataggacca ctgaagagcg tcatgttccggggtggtatt gtaaatcacc cagtcgtagc 3120 agggtttttg agcgtggaac tggaatatgtccttcaggag caggctaatg gccaagggta 3180 gacccttagt gtaggtgttt acaaagcggttgagctggga gggatgcatg cggggggaga 3240 tgatatgcat cttggcttgg attttgaggttagctatgtt accacccagg tctctgcggg 3300 ggttcatgtt atgaaggacc accagcacggtatagccagt gcatttgggg aacttgtcat 3360 gcagtttgga ggggaaggcg tggaagaatttagatacccc cttgtgcccc cctaggtttt 3420 ccatgcactc atccataata atggcaatgggacccctggc ggccgcttta gcaaacacgt 3480 tttgggggtt ggaaacatca tagttttgctctagagtgag ctcatcatag gccatcttta 3540 caaagcgggg taggagggtg cccgactgggggatgatagt tccatctggg cctggagcgt 3600 agttgccctc acagatctgc atctcccaggccttaatttc cgaggggggg atcatgtcca 3660 cctggggggc gataaaaaac acggtttctggcggggggtt aatgagctgg gtggaaagca 3720 agttacgcaa cagctgggat ttgccgcaaccggtgggacc gtagatgacc ccgatgacgg 3780 gttgcagctg gtagttcaga gaggaacagctgccgtcggg gcgcaggagg ggagctacct 3840 cattcatcat gcttctgaca tgtttattttcactcactaa gttttgcaag agcctctccc 3900 cacccaggga taagagttct tccaggctgttgaagtgttt cagcggtttc aggccgtcgg 3960 ccatgggcat cttttcaagc gactgacgaagcaagtacag tcggtcccag agctcggtga 4020 cgtgctctat ggaatctcga tccagcagacttcttggttt cgggggttgg gccgactttc 4080 gctgtagggc accagccggt gggcgtccagggccgcgagg gttctgtcct tccagggtct 4140 cagcgttcgg gtgagggtgg tctcggtgacggtgaaggga tgagccccgg gctgggcgct 4200 tgcgagggtg cgcttcaggc tcatcctgctggtgctgaag cgggcgtcgt ctccctgtga 4260 gtcggccaga tagcaacgaa gcatgaggtcgtagctgagg gactcggccg cgtgtccctt 4320 ggcgcgcagc tttcccttgg aaacgtgctgacatttggtg cagtgcagac acttgagggc 4380 gtagagtttt ggggccagga agaccgactcgggcgagtag gcgtcggctc cgcactgagc 4440 gcagacggtc tcgcactcca ccagccacgtgagctcgggt ttagcgggat caaaaaccaa 4500 gttgcctcca ttttttttga tgcgtttcttaccttgcgtc tccatgagtc tgtgtcccgc 4560 ttccgtgaca aaaaggctgt cggtatccccgtagaccgac ttgagggggc gatcttccaa 4620 aggtgttccg aggtcttccg cgtacaggaactgggaccac tccgagacaa aggctcgggt 4680 ccaggctaac acgaaggagg cgatctgcgaggggtatctg tcgttttcaa tgagggggtc 4740 caccttttcc agggtgtgca gacacaggtcgtcctcctcc gcgtccacga aggtgattgg 4800 cttgtaagtg taggtcacgt gacccgcacccccccaaggg gtataaaagg gggcgtgccc 4860 actctccccg tcactttctt ccgcatcgctgtggaccaga gccagctgtt cgggtgagta 4920 ggccctctca aaagccggca tgatttcggcgctcaagttg tcagtttcta caaacgaggt 4980 ggatttgata ttcacgtgcc ccgcggcgatgcttttgatg gtggaggggt ccatctgatc 5040 agaaaacacg atctttttat tgtcaagtttggtggcgaaa gacccgtaga gggcgttgga 5100 aagcaacttg gcgatggagc gcagggtctgatttttctcc cgatcggccc tctccttggc 5160 ggcgatgttg agttgcacgt actcgcgggccacgcaccgc cactcgggga acacggcggt 5220 gcgctcgtcg ggcaggatgc gcacgcgccagccgcggttg tgcagggtga tgaggtccac 5280 gctggtggcc acctccccgc ggaggggctcgttggtccaa cacaatcgcc ccccttttct 5340 ggagcagaac ggaggcaggg gatctagcaagttggcgggc ggggggtcgg cgtcgatggt 5400 aaatatgccg ggtagcagaa ttttattaaaataatcgatt tcggtgtccg tgtcttgcaa 5460 cgcgtcttcc cacttcttca ccgccagggccctttcgtag ggattcaggg gcggtcccca 5520 gggcatgggg tgggtcaggg ccgaggcgtacatgccgcag atgtcgtaca cgtacagggg 5580 ctccctcaac accccgatgt aagtggggtaacagcgcccc ccgcggatgc tggctcgcac 5640 gtagtcgtac atctcgtgag agggagccatgagcccgtct cccaagtggg tcttgtgggg 5700 tttttcggcc cggtagagga tctgcctgaagatggcgtgg gagttggaag agatagtggg 5760 gcgttggaag acgttaaagt tggctccgggcagtcccacg gagtcttgga tgaactgggc 5820 gtaggattcc cggagcttgt ccaccagggctgcggttacc agcacgtcga gagcgcagta 5880 gtccaacgtc tcgcggacca ggttgtaggccgtctcttgt tttttctccc acagttcgcg 5940 attgaggagg tattcctcgc ggtctttccagtactcttcg gcgggaaatc ctttttcgtc 6000 cgctcggtaa gaacctaaca tgtaaaattcgttcacggct ttgtatggac aacagccttt 6060 ttctaccggc agggcgtacg cttgagcggcctttctgaga gaggtgtggg tgagggcgaa 6120 ggtgtcccgc accatcactt tcaggtactgatgtttgaag tccgtgtcgt cgcaggcgcc 6180 ctgttcccac agcgtgaagt cggtgcgctttttctgcctg ggattgggga gggcgaatgt 6240 gacgtcgtta aagaggattt tcccggcgcggggcatgaag ttgcgagaga tcctgaaggg 6300 tccgggcacg tccgagcggt tgttgatgacttgcgccgcc aggacgatct cgtcgaagcc 6360 gttgatgttg tggcccacga tgtaaagttcgataaagcgc ggctgtccct tgagggccgg 6420 cgcttttttc aactcctcgt aggtgagacagtccggcgag gagagaccca gctccgcccg 6480 ggcccagtcg gagagctgag ggttagccgcgaggaaagag ctccacaggt caagggctag 6540 cagagtttgc aagcggtcgc ggaactcgcgaaactttttc cccacggcca ttttctccgg 6600 cgtcaccacg tagaaagtgc aggggcggtcgttccagacg tcccatcgga gctctagggc 6660 cagctcgcag gcttgacgaa cgagggtctcctcgcccgag acgtgcatga ccagcatgaa 6720 gggtaccaac tgtttcccga acgagcccatccatgtgtag gtttctacgt cgtaggtgac 6780 aaagagccgc tgggtgcgcg cgtgggagccgatcgggaag aagctgatct cctgccacca 6840 gttggaggaa tgggtgttga tgtggtgaaagtagaagtcc cgccggcgca cagagcattc 6900 gtgctgatgt ttgtaaaagc gaccgcagtagtcgcagcgc tgcacgctct gtatctcctg 6960 aatgagatgc gcttttcgcc cgcgcaccagaaaccggagg gggaagttga gacgggggct 7020 tggtggggcg gcatcccctt cgccttggcggtgggagtct gcgtctgcgc cctccttctc 7080 tgggtggacg acggtgggga cgacgacgccccgggtgccg caagtccaga tctccgccac 7140 ggaggggcgc aggcgttgca ggaggggacgcagctgcccg ctgtccaggg agtcgagggc 7200 ggccgcgctg aggtcggcgg gaagcgtttgcaagttcact ttcagaagac cggtaagagc 7260 gtgagccagg tgcacatggt acttgatttccaggggggtg ttggaagagg cgtccacggc 7320 gtagaggagg ccgtgtccgc gcggggccaccaccgtgccc cgaggaggtt ttatctcact 7380 cgtcgagggc gagcgccggg gggtagaggcggctctgcgc cggggggcag cggaggcagt 7440 ggcacgtttt cgtgaggatt cggcagcggttgatgacgag cccggagact gctggcgtgg 7500 gcgacgacgc ggcggttgag gtcctggatgtgccgtctct gcgtgaagac caccggcccc 7560 cgggtcctga acctgaaaga gagttccacagaatcaatgt ctgcatcgtt aacggcggcc 7620 tgcctgagga tctcctgtac gtcgcccgagttgtcttgat aggcgatctc ggccatgaac 7680 tgctccactt cttcctcgcg gaggtcgccgtggcccgctc gctccacggt ggcggccagg 7740 tcgttggaga tgcgacgcat gagttgagagaaggcgttga ggccgttctc gttccacacg 7800 cggctgtaca ccacgtttcc gaaggagtcgcgcgctcgca tgaccacctg ggccacgttg 7860 agttccacgt ggcgggcgaa gacggcgtagtttctgaggc gctggaagag gtagttgagc 7920 gtggtggcga tgtgctcgca gacgaagaagtacatgatcc agcgccgcag ggtcatctcg 7980 ttgatgtctc cgatggcttc gagacgctccatggcctcgt agaagtcgac ggcgaagttg 8040 aaaaattggg agttgcgggc ggccaccgtgagttcttctt gcaggaggcg gatgagatcg 8100 gcgaccgtgt cgcgcacctc ctgctcgaaagcgccccgag gcgcctctgc ttcttcctcc 8160 ggctcctcct cttccagggg cacgggttcctccggcagct ctgcgacggg gacggggcgg 8220 cgacgtcgtc gtctgaccgg caggcggtccacgaagcgct cgatcatttc gccgcgccgg 8280 cgacgcatgg tctcggtgac ggcgcgtccgttttcgcgag gtcgcagttc gaagacgccg 8340 ccgcgcagag cgcccccgtg cagggagggtaagtggttag ggccgtcggg cagggacacg 8400 gcgctgacga tgcattttat caattgctgcgtaggcactc cgtgcaggga tctgagaacg 8460 tcgaggtcga cgggatccga gaacttctctaggaaagcgt ctatccaatc gcagtcgcaa 8520 ggtaagctga ggacggtggg ccgctggggggcgtccgcgg gcagttggga ggtgatgctg 8580 ctgatgatgt aattaaagta ggcggtcttcaggcggcgga tggtggcgag gaggaccacg 8640 tctttgggcc cggcctgttg aatgcgcaggcgctcggcca tgccccaggc ctcgctctga 8700 cagcgacgca ggtctttgta gtagtcttgcatcagtctct ccaccggaac ctctgcttct 8760 cccctgtctg ccatgcgagt cgagccgaacccccgcaggg gctgcagcaa cgctaggtcg 8820 gccacgaccc tctcggccag cacggcctgttggatctgcg tgagggtggt ctggaagtcg 8880 tccaggtcca cgaagcggtg ataggcccccgtgttgatgg tgtaggtgca gttggccatg 8940 acggaccagt tgacgacttg catgccgggttgggtgatct ccgtgtactt gaggcgcgag 9000 taggcgcggg actcgaacac gtagtcgttgcatgtgcgta ccagatactg gtagccaacc 9060 aggaagtggg gaggcggttc tcggtacaggggccagccga ctgtggcggg ggcgccgggg 9120 gacaggtcgt ccagcatgag gcgatggtagtggtagatgt agcgggagag ccaggtgatg 9180 ccggccgagg tggtcgcggc cctggtgaattcgcggacgc ggttccagat gttgcgcagg 9240 gggcgaaagc gctccatggt gggcacgctctgccccgtga ggcgggcgca atcttgtacg 9300 ctctagatgg aaaaaagaca gggcggtcatcgactccctt ccgtagctcg gggggtaaag 9360 tcgcaagggt gcggcggcgg ggaaccccggttcgagaccg gccggatccg ccgctcccga 9420 tgcgcctggc cccgcatcca cgacgtccgcgtcgagaccc agccgcgacg ctccgcccca 9480 atacggaggg gagtcttttg gtgttttttcgtagatgcat ccggtgctgc ggcagatgcg 9540 acctcagacg cccaccacca ccgccgcggcggcagtaaac ctgagcggag gcggtgacag 9600 ggaggaggag gagctggctt tagacctggaagagggagag gggctggccc ggctgggagc 9660 gccgtcccca gagagacacc ctagggttcagctcgtgagg gacgccaggc aggcttttgt 9720 gccgaagcag aacctgttta gggaccgcagcggtcaggag gcggaggaga tgcgcgattg 9780 caggtttcgg gcgggtagag agctgagggcgggcttcgat cgggagcggc tcctgagggc 9840 ggaggatttc gagcccgacg agcgttctggggtgagcccg gcccgcgctc acgtctcggc 9900 ggccaacctg gtgagcgcgt acgagcagacggtgaacgag gagcgcaact tccaaaagag 9960 ctttaacaat cacgtgagga ccctgatcgcgagggaggag gtgaccatcg ggctgatgca 10020 tctgtgggac ttcgtggagg cctacgtgcagaacccggcc agcaaacctc tgacggccca 10080 gctgttcctg atcgtgcagc acagccgcgacaacgagacg ttccgcgacg ccatgttgaa 10140 catcgcggag cccgagggtc gctggctcttggatctgatt aacatcctgc agagcatcgt 10200 ggtgcaggag aggggcctca gcttagcggacaaggtggcg gccattaact attcgatgca 10260 gagcctgggg aagttctacg ctcgcaagatctacaagagc ccttacgtgc ccatagacaa 10320 ggaggtgaag atagacagct tttacatgcgcatggcgctg aaggtgctga cgctgagcga 10380 cgacctcggc gtgtaccgta acgacaagatccacaaggcg gtgagcgcca gccgccggcg 10440 ggagctgagc gacagggagc tgatgcacagcctgcagagg gcgctggcgg gcgccgggga 10500 cgaggagcgc gaggcttact tcgacatgggagccgatctg cagtggcgtc ccagcgcgcg 10560 cgccttggag gcggcgggct accccgacgaggaggatcgg gacgatttgg aggaggcagg 10620 cgagtacgag gacgaagcct gaccgggcaggtgttgtttt agatgcagcg gccggcggac 10680 ggggccaccg cggatcccgc acttttggcatccatgcaga gtcaaccttc gggcgtgacc 10740 gcctccgatg actgggcggc ggccatggaccgcattatgg cgctgactac ccgcaacccc 10800 gaggctttta gacagcaacc ccaggccaaccgtttttcgg ccatcttgga agcggtggtg 10860 ccctcccgca ccaaccccac acacgagaaagtcctgacta tcgtgaacgc cctggtagac 10920 agcaaggcca tccgccgcga cgaggcgggcttgatttaca acgctctgct ggaacgggtg 10980 gcgcgctaca acagcactaa cgttcagaccaatctggatc gcctcaccac cgacgtgaag 11040 gaggcgctgg ctcagaagga gcggtttctgagggacagca atctgggctc tctggtggca 11100 ctcaacgcct tcctgagcac gcagccggccaacgtgcccc gcgggcagga ggactacgtg 11160 agcttcatca gcgctctgag gctgctggtgtccgaggtgc cccagagcga ggtgtatcag 11220 tctgggccgg attacttctt ccagacgtcccgacagggct tgcaaacggt gaacctgact 11280 caggccttta aaaacttgca aggcatgtggggcgttaagg ccccggtggg cgatcgagcc 11340 accatctcca gtctgctgac ccccaacactcgcctgctgc tgctcttgat cgcgccgttc 11400 accaacagta gcactatcag ccgtgactcgtacctgggtc atctcatcac tttgtaccgc 11460 gaggccatcg gtcaggctca gatcgacgagcacacatatc aggagatcac taacgtgagc 11520 cgggccctgg gtcaggaaga taccggcagcctggaagcca cgttgaactt tttgctaacc 11580 aaccggaggc aaaaaatacc ctcccagtttacgttaagcg ccgaggagga gaggattctg 11640 cgatacgtgc agcagtccgt gagtctgtacttgatgcggg agggcgccac cgcttccacg 11700 gctttagaca tgacggctcg gaacatggaaccgtcctttt actccgccca ccggccgttc 11760 attaaccgtc tgatggacta cttccatcgcgcggccgcca tgaacgggga gtacttcacc 11820 aatgccatcc tgaatccgca ttggatgcccccgtccggct tctacaccgg cgagtttgac 11880 ctgcccgaag ccgacgacgg ctttctttgggacgacgtgt ccgacagcat tttcacgccg 11940 ggcaatcgcc gattccagaa gaaggagggcggagacgagc tccccctctc cagcgtggag 12000 gcggcctcta ggggagagag tccctttcccagtctgtctt ccgccagcag tggtcgggta 12060 acgcgcccgc ggttgccggg ggagagcgactacctgaacg accccttgct gcggccggct 12120 aggaagaaaa atttccccaa caacggggtggaaagcttgg tggataaaat gaatcgttgg 12180 aagacctacg cccaggagca gcgggagtgggaggacagtc agccgcgacc gctggttccg 12240 ccgcactggc gtcgtcagag agaagacccggacgactccg cagacgatag tagcgtgttg 12300 gacctgggag ggagcggagc caacccctttgctcacttgc aacccaaggg gcgttccagt 12360 cgcctctact aataaaaaag acgcggaaacttaccagagc catggccaca gcgtgtgtcc 12420 tttcttcctc tctttcttcc tcggcgcggcaga atg aga aga gcg gtg aga gtc 12474 Met Arg Arg Ala Val Arg Val 1 5acg ccg gcg gcg tat gag ggt ccg ccc cct tct tac gaa agc gtg atg 12522Thr Pro Ala Ala Tyr Glu Gly Pro Pro Pro Ser Tyr Glu Ser Val Met 10 15 20gga tca gcg aac gtg ccg gcc acg ctg gag gcg cct tac gtt cct ccc 12570Gly Ser Ala Asn Val Pro Ala Thr Leu Glu Ala Pro Tyr Val Pro Pro 25 30 35aga tac ctg gga cct acg gag ggc aga aac agc atc cgt tac tcc gag 12618Arg Tyr Leu Gly Pro Thr Glu Gly Arg Asn Ser Ile Arg Tyr Ser Glu 40 45 5055 ctg gca ccc ctg tac gat acc acc aag gtg tac ctg gtg gac aac aag 12666Leu Ala Pro Leu Tyr Asp Thr Thr Lys Val Tyr Leu Val Asp Asn Lys 60 65 70tcg gcg gac atc gcc tcc ctg aat tat caa aac gat cac agc aat ttt 12714Ser Ala Asp Ile Ala Ser Leu Asn Tyr Gln Asn Asp His Ser Asn Phe 75 80 85ctg act acc gtg gtg cag aac aat gac ttc acc ccg acg gag gcg ggc 12762Leu Thr Thr Val Val Gln Asn Asn Asp Phe Thr Pro Thr Glu Ala Gly 90 95100 acg cag acc att aac ttt gac gag cgt tcc cgc tgg ggc ggt cag ctg12810 Thr Gln Thr Ile Asn Phe Asp Glu Arg Ser Arg Trp Gly Gly Gln Leu105 110 115 aaa acc atc ctg cac acc aac atg ccc aac atc aac gag ttc atgtcc 12858 Lys Thr Ile Leu His Thr Asn Met Pro Asn Ile Asn Glu Phe MetSer 120 125 130 135 acc aac aag ttc agg gcc agg ctg atg gtt aaa aag gctgaa aac cag 12906 Thr Asn Lys Phe Arg Ala Arg Leu Met Val Lys Lys AlaGlu Asn Gln 140 145 150 cct ccc gag tac gaa tgg ttt gag ttc acc att cccgag ggc aac tat 12954 Pro Pro Glu Tyr Glu Trp Phe Glu Phe Thr Ile ProGlu Gly Asn Tyr 155 160 165 tcc gag acc atg act atc gat ctg atg aac aatgcg atc gtg gac aat 13002 Ser Glu Thr Met Thr Ile Asp Leu Met Asn AsnAla Ile Val Asp Asn 170 175 180 tac ctg caa gtg ggg agg cag aac ggg gtattg gaa agc gat atc ggc 13050 Tyr Leu Gln Val Gly Arg Gln Asn Gly ValLeu Glu Ser Asp Ile Gly 185 190 195 gta aaa ttt gat acc aga aac ttc cgactg ggg tgg gat ccc gtg acc 13098 Val Lys Phe Asp Thr Arg Asn Phe ArgLeu Gly Trp Asp Pro Val Thr 200 205 210 215 aag ctg gtg atg cca ggc gtgtac acc aac gag gct ttt cac ccc gac 13146 Lys Leu Val Met Pro Gly ValTyr Thr Asn Glu Ala Phe His Pro Asp 220 225 230 atc gtg ctg ctg ccg gggtgc ggt gtg gac ttc act cag agc cgt ttg 13194 Ile Val Leu Leu Pro GlyCys Gly Val Asp Phe Thr Gln Ser Arg Leu 235 240 245 agt aac ctg tta gggatc aga aag cgc cgc ccc ttc caa gag ggc ttt 13242 Ser Asn Leu Leu GlyIle Arg Lys Arg Arg Pro Phe Gln Glu Gly Phe 250 255 260 cag atc atg tatgag gac ctg gaa gga ggt aac att cca ggt ttg cta 13290 Gln Ile Met TyrGlu Asp Leu Glu Gly Gly Asn Ile Pro Gly Leu Leu 265 270 275 gac gtg ccggcg tat gaa gag agt gtt aaa cag gcg gag gcg cag gga 13338 Asp Val ProAla Tyr Glu Glu Ser Val Lys Gln Ala Glu Ala Gln Gly 280 285 290 295 cgagag att cga ggc gac acc ttt gcc acg gaa cct cac gaa ctg gta 13386 ArgGlu Ile Arg Gly Asp Thr Phe Ala Thr Glu Pro His Glu Leu Val 300 305 310ata aaa cct ctg gaa caa gac agt aaa aaa cgg agt tac aac att ata 13434Ile Lys Pro Leu Glu Gln Asp Ser Lys Lys Arg Ser Tyr Asn Ile Ile 315 320325 tcc ggc act atg aat acc ttg tac cgg agc tgg ttt ctg gct tac aac13482 Ser Gly Thr Met Asn Thr Leu Tyr Arg Ser Trp Phe Leu Ala Tyr Asn330 335 340 tac ggg gat ccc gaa aag gga gtg aga tca tgg acc ata ctc accacc 13530 Tyr Gly Asp Pro Glu Lys Gly Val Arg Ser Trp Thr Ile Leu ThrThr 345 350 355 acg gac gtg acc tgc ggc tcg cag caa gtg tac tgg tcc ctgccg gat 13578 Thr Asp Val Thr Cys Gly Ser Gln Gln Val Tyr Trp Ser LeuPro Asp 360 365 370 375 atg atg caa gac ccg gtc acc ttc cgc ccc tcc acccaa gtc agc aac 13626 Met Met Gln Asp Pro Val Thr Phe Arg Pro Ser ThrGln Val Ser Asn 380 385 390 ttc ccg gtg gtg ggc acc gag ctg ctg ccc gtccat gcc aag agc ttc 13674 Phe Pro Val Val Gly Thr Glu Leu Leu Pro ValHis Ala Lys Ser Phe 395 400 405 tac aac gaa cag gcc gtc tac tcg caa ctcatt cgc cag tcc acc gcg 13722 Tyr Asn Glu Gln Ala Val Tyr Ser Gln LeuIle Arg Gln Ser Thr Ala 410 415 420 ctt acc cac gtg ttc aat cgc ttt cccgag aac cag att ctg gtg cgc 13770 Leu Thr His Val Phe Asn Arg Phe ProGlu Asn Gln Ile Leu Val Arg 425 430 435 cct ccc gct cct acc att acc accgtc agt gaa aac gtt ccc gcc ctc 13818 Pro Pro Ala Pro Thr Ile Thr ThrVal Ser Glu Asn Val Pro Ala Leu 440 445 450 455 aca gat cac gga acc ctgccg ctg cgc agc agt atc agt gga gtt cag 13866 Thr Asp His Gly Thr LeuPro Leu Arg Ser Ser Ile Ser Gly Val Gln 460 465 470 cgc gtg acc atc accgac gcc aga cgt cga acc tgt ccc tac gtt tac 13914 Arg Val Thr Ile ThrAsp Ala Arg Arg Arg Thr Cys Pro Tyr Val Tyr 475 480 485 aaa gct ctt ggcgta gtg gct cct aaa gtg ctc tct agt cgc acc ttc 13962 Lys Ala Leu GlyVal Val Ala Pro Lys Val Leu Ser Ser Arg Thr Phe 490 495 500 taaacatgtccat cctcatctct cccgataaca acaccggctg gggactgggc 14015 tccggcaagatgtacggcgg agccaaaagg cgctccagtc agcacccagt tcgagttcgg 14075 ggccacttccgtgctccctg gggagcttac aagcgaggac tctcgggccg aacggcggta 14135 gacgataccatagatgccgt gattgccgac gcccgccggt acaaccccgg accggtcgct 14195 agcgccgcctccaccgtgga ttccgtgatc gacagcgtgg tagctggcgc tcgggcctat 14255 gctcgccgcaagaggcggct gcatcggaga cgtcgcccca ccgccgccat gctggcagcc 14315 agggccgtgctgaggcgggc ccggagggta ggcagaaggg ctatgcgccg cgctgccgcc 14375 aacgccgccgccgggagggc ccgccgacag gctgcccgcc aggctgctgc cgccatcgct 14435 agcatggccagacccaggag agggaacgtg tactgggtgc gcgattctgt gacgggagtc 14495 cgagtgccggtgcgcagccg acctccccga agttagaaga tccaagctgc gaagacggcg 14555 gtactgagtctccctgttgt tatcagccca acatgagcaa gcgcaagttt aaagaagaac 14615 tgctgcagacgctggtgcct gagatctatg gccctccgga cgtgaagcct gacattaagc 14675 cccgcgatatcaagcgtgtt aaaaagcggg aaaagaaaga ggaactcgcg gtggtagacg 14735 atggcggagtggaatttatt aggagtttcg ccccgcgacg cagggttcaa tggaaagggc 14795 ggcgggtacaacgcgttttg aggccgggca ccgcggtagt ttttaccccg ggagagcggt 14855 cggccgttaggggtttcaaa aggcagtacg acgaggtgta cggcgacgag gacatattgg 14915 aacaggcggctcaacagatc ggagaatttg cctacggaaa gcgttcgcgt cgcgaagacc 14975 tggccatcgctttagacagc ggcaacccca cgcccagcct caaacctgtg acgctgcagc 15035 aggtgctccccgtgagcgcc agcacggaca gcaagagggg aataaaaaga gaaatggaag 15095 atctgcagcccaccatccag ctcatggtcc ctaaacggca gaggctggaa gaggtcctgg 15155 agaaaatgaaagtggaccca agcatagagc cggacgtcaa agtcaggccg atcaaagaag 15215 tggcccctggtctcggggtg cagacggtgg atatccagat ccccgtcacg tcagcttcga 15275 ccgccgtggaagccatggaa acgcaaacgg aaacccctgc cgcgatcggt accagggaag 15335 tggcgttgcaaaccgacccc tggtacgaat acgccgcccc tcggcgtcag aggcgacccg 15395 ctcgttacggccccgccaac gccatcatgc cagaatatgc gctgcatccg tctatcctgc 15455 ccacccccggctaccgggga gtgacgtatc gcccgtcagg aacccgccgc cgaacccgtc 15515 gccgccgccgctcccgtcgt gctctggccc ccgtgtcggt gcgccgcgta acacgccggg 15575 gaaagacagttaccattccc aacccgcgct accaccctag catcctttaa tgactctgcc 15635 gttttgcagatggctctgac ttgccgcgtg cgccttcccg ttccgcacta tcgaggaaga 15695 tctcgtcgtaggagaggcat ggcgggtagt ggtcgccggc gggctttgcg caggcgcatg 15755 aaaggcggaattttacccgc tctgataccc ataatcgccg ccgccatcgg tgccataccc 15815 ggcgtcgcttcagtggcctt gcaagcagct cgtaataaat aaacgaaggc ttttgcactt 15875 atgtcctggtcctgactatt ttatgcagaa agagcatgga agacatcaat tttacgtcgc 15935 tggctccgcggcacggctcg cggccgctca tgggcacctg gaacgacatc ggcaccagtc 15995 agctcaacgggggcgctttc aattggggga gcctttggag cggcattaaa aactttggct 16055 ccacgattaaatcctacggc agcaaagcct ggaacagtag tgctggtcag atgctccgag 16115 ataaactgaaggacaccaac ttccaagaaa aagtggtcaa tggggtggtg accggcatcc 16175 acggcgcggtagatctcgcc aaccaagcgg tgcagaaaga gattgacagg cgtttggaaa 16235 gctcgcgggtgccgccgcag agaggggatg aggtggaggt cgaggaagta gaagtagagg 16295 aaaagctgcccccgctggag aaagttcccg gtgcgcctcc gagaccgcag aagcgaccca 16355 ggccagaactagaagaaact ctggtgacgg agagcaagga gcctccctcg tacgagcaag 16415 ccttgaaagagggcgcctct ccaccctacc caatgacaaa accgatcgcg cctatggctc 16475 ggccggtgtacgggaaggac tacaagcctg tcacgctaga gctccccccg ccgccaccgc 16535 cgccccccacgcgcccgacc gttccccccc ccctgccggc tccgtcggcg ggacccgtgt 16595 ccgcacccgtcgccgtgcct ctgccagccg cccgcccagt ggccgtggcc actgccagaa 16655 accccagaggccagagagga gccaactggc aaagcacgct gaacagcatc gtgggcctgg 16715 gagtgaaaagcctgaaacgc cgccgttgct attattaaaa gtgtagctaa aaaatttccc 16775 gttgtatacgcctcctatgt taccgccaga gacgcgtgac tgtcgccgcg agcgccgctt 16835 tcaag atggcc acc cca tcg atg atg ccg cag tgg tct tac atg cac atc 16885 Met AlaThr Pro Ser Met Met Pro Gln Trp Ser Tyr Met His Ile 505 510 515 gcc gggcag gac gcc tcg gag tac ctg agc ccc ggt ctc gtg cag ttc 16933 Ala GlyGln Asp Ala Ser Glu Tyr Leu Ser Pro Gly Leu Val Gln Phe 520 525 530 gcccgc gcc acc gac acc tac ttc agc ttg gga aac aag ttt aga aac 16981 AlaArg Ala Thr Asp Thr Tyr Phe Ser Leu Gly Asn Lys Phe Arg Asn 535 540 545550 ccc acc gtg gcc ccc acc cac gat gta acc acg gac cgc tcg caa agg17029 Pro Thr Val Ala Pro Thr His Asp Val Thr Thr Asp Arg Ser Gln Arg555 560 565 ctg acc ctg cgt ttt gtg ccc gta gac cgg gag gac acc gcg tactct 17077 Leu Thr Leu Arg Phe Val Pro Val Asp Arg Glu Asp Thr Ala TyrSer 570 575 580 tac aaa gtg cgc tac acg ctg gcc gta ggg gac aac cga gtgctg gac 17125 Tyr Lys Val Arg Tyr Thr Leu Ala Val Gly Asp Asn Arg ValLeu Asp 585 590 595 atg gcc agc acc tac ttt gac atc cgg gga gtg ctg gatcgc ggt ccc 17173 Met Ala Ser Thr Tyr Phe Asp Ile Arg Gly Val Leu AspArg Gly Pro 600 605 610 agt ttt aag ccc tac tcg ggt acc gcg tac aat tccctg gct ccc aag 17221 Ser Phe Lys Pro Tyr Ser Gly Thr Ala Tyr Asn SerLeu Ala Pro Lys 615 620 625 630 ggc gct ccc aac cct gca gaa tgg acg aattca gac agc aaa gtt aaa 17269 Gly Ala Pro Asn Pro Ala Glu Trp Thr AsnSer Asp Ser Lys Val Lys 635 640 645 gtg agg gca cag gcg cct ttt gtt agctcg tat ggt gct aca gcg att 17317 Val Arg Ala Gln Ala Pro Phe Val SerSer Tyr Gly Ala Thr Ala Ile 650 655 660 aca aaa gag ggt att cag gtg ggagta acc tta aca gac tcc gga tca 17365 Thr Lys Glu Gly Ile Gln Val GlyVal Thr Leu Thr Asp Ser Gly Ser 665 670 675 aca cca cag tat gca gat aaaacg tat cag cct gag ccg caa att gga 17413 Thr Pro Gln Tyr Ala Asp LysThr Tyr Gln Pro Glu Pro Gln Ile Gly 680 685 690 gaa cta cag tgg aac agcgat gtt gga acc gat gac aaa ata gca gga 17461 Glu Leu Gln Trp Asn SerAsp Val Gly Thr Asp Asp Lys Ile Ala Gly 695 700 705 710 aga gtg cta aagaaa aca acg ccc atg ttc cct tgt tac ggc tca tat 17509 Arg Val Leu LysLys Thr Thr Pro Met Phe Pro Cys Tyr Gly Ser Tyr 715 720 725 gcc agg cccact aat gaa aaa gga gga cag gca aca ccg tcc gct agt 17557 Ala Arg ProThr Asn Glu Lys Gly Gly Gln Ala Thr Pro Ser Ala Ser 730 735 740 caa gacgtg caa aat ccc gaa tta caa ttt ttt gcc tct act aat gtc 17605 Gln AspVal Gln Asn Pro Glu Leu Gln Phe Phe Ala Ser Thr Asn Val 745 750 755 gccaat aca cca aaa gca gtt cta tat gcg gag gac gtg tca att gaa 17653 AlaAsn Thr Pro Lys Ala Val Leu Tyr Ala Glu Asp Val Ser Ile Glu 760 765 770gcg cca gac act cac ttg gtg ttc aaa cca aca gtc act gaa ggc att 17701Ala Pro Asp Thr His Leu Val Phe Lys Pro Thr Val Thr Glu Gly Ile 775 780785 790 aca agt tca gag gct cta ctg acc caa caa gct gct ccc aac cgt cca17749 Thr Ser Ser Glu Ala Leu Leu Thr Gln Gln Ala Ala Pro Asn Arg Pro795 800 805 aac tac ata gcc ttt aga gat aat ttt att ggt ctc atg tac tacaat 17797 Asn Tyr Ile Ala Phe Arg Asp Asn Phe Ile Gly Leu Met Tyr TyrAsn 810 815 820 agc aca ggt aac atg gga gta ctg gca ggc cag gct tct cagcta aat 17845 Ser Thr Gly Asn Met Gly Val Leu Ala Gly Gln Ala Ser GlnLeu Asn 825 830 835 gca gtt gtt gac ctg caa gac aga aat act gag ctg tcctac caa ctc 17893 Ala Val Val Asp Leu Gln Asp Arg Asn Thr Glu Leu SerTyr Gln Leu 840 845 850 atg ttg gac gcc ctc gga gac cgc agt cgg tac ttttct atg tgg aac 17941 Met Leu Asp Ala Leu Gly Asp Arg Ser Arg Tyr PheSer Met Trp Asn 855 860 865 870 caa gct gtg gat agt tac gat cct gat gtaaga atc ata gaa aac cat 17989 Gln Ala Val Asp Ser Tyr Asp Pro Asp ValArg Ile Ile Glu Asn His 875 880 885 ggc gta gaa gat gaa ttg cct aat tattgc ttt cct ttg gga ggc atg 18037 Gly Val Glu Asp Glu Leu Pro Asn TyrCys Phe Pro Leu Gly Gly Met 890 895 900 gca gta acc gac acc tac tcg cctata aag gtt aat gga gga ggc aat 18085 Ala Val Thr Asp Thr Tyr Ser ProIle Lys Val Asn Gly Gly Gly Asn 905 910 915 gga tgg gaa gcc aat aac ggcgtt ttc acc gaa aga gga gtg gaa ata 18133 Gly Trp Glu Ala Asn Asn GlyVal Phe Thr Glu Arg Gly Val Glu Ile 920 925 930 ggt tca ggg aac atg tttgcc atg gag att aac ctg caa gcc aac cta 18181 Gly Ser Gly Asn Met PheAla Met Glu Ile Asn Leu Gln Ala Asn Leu 935 940 945 950 tgg cgt agc tttctg tac tcc aat att ggg ctg tac ctg cca gac tct 18229 Trp Arg Ser PheLeu Tyr Ser Asn Ile Gly Leu Tyr Leu Pro Asp Ser 955 960 965 ctc aaa atcact cct gac aac atc aca ctc cca gag aac aaa aac acc 18277 Leu Lys IleThr Pro Asp Asn Ile Thr Leu Pro Glu Asn Lys Asn Thr 970 975 980 tat cagtat atg aac ggt cgc gtg acg cca ccc ggg ctg gtt gac acc 18325 Tyr GlnTyr Met Asn Gly Arg Val Thr Pro Pro Gly Leu Val Asp Thr 985 990 995 tacgtt aac gtg ggc gcg cgc tgg tcc ccc gat gtc atg gac agt 18370 Tyr ValAsn Val Gly Ala Arg Trp Ser Pro Asp Val Met Asp Ser 1000 1005 1010 attaac cct ttt aat cac cac cgc aac gcc gga ctc cgc tac cgt 18415 Ile AsnPro Phe Asn His His Arg Asn Ala Gly Leu Arg Tyr Arg 1015 1020 1025 tccatg ctc ctg gga aac gga cgc tac gtg ccc ttc cac atc cag 18460 Ser MetLeu Leu Gly Asn Gly Arg Tyr Val Pro Phe His Ile Gln 1030 1035 1040 gtgccc cag aaa ttc ttt gca att aaa aac ctg ctg ctg ctc ccc 18505 Val ProGln Lys Phe Phe Ala Ile Lys Asn Leu Leu Leu Leu Pro 1045 1050 1055 ggttcc tac acc tac gag tgg aac ttc cgc aag gac gtg aac atg 18550 Gly SerTyr Thr Tyr Glu Trp Asn Phe Arg Lys Asp Val Asn Met 1060 1065 1070 atcttg cag agc tcg ctg ggc aat gac ctg cga gtg gac ggg gcc 18595 Ile LeuGln Ser Ser Leu Gly Asn Asp Leu Arg Val Asp Gly Ala 1075 1080 1085 agcatc cgc ttc gac agc atc aac ctg tac gcc aac ttt ttc ccc 18640 Ser IleArg Phe Asp Ser Ile Asn Leu Tyr Ala Asn Phe Phe Pro 1090 1095 1100 atggcc cac aac acg gcc tcc acc ctg gaa gcc atg ctg cgc aac 18685 Met AlaHis Asn Thr Ala Ser Thr Leu Glu Ala Met Leu Arg Asn 1105 1110 1115 gacacc aac gac caa tct ttc aac gac tac ctg tgc gcg gcc aac 18730 Asp ThrAsn Asp Gln Ser Phe Asn Asp Tyr Leu Cys Ala Ala Asn 1120 1125 1130 atgctg tac ccc atc ccc gcc aac gcc acc agc gtg ccc atc tcc 18775 Met LeuTyr Pro Ile Pro Ala Asn Ala Thr Ser Val Pro Ile Ser 1135 1140 1145 attccc tct cgc aac tgg gca gcc ttc agg ggc tgg agt ttc acc 18820 Ile ProSer Arg Asn Trp Ala Ala Phe Arg Gly Trp Ser Phe Thr 1150 1155 1160 cgcctc aaa acc aag gag acc ccc tcg ctg ggc tcc ggg ttc gac 18865 Arg LeuLys Thr Lys Glu Thr Pro Ser Leu Gly Ser Gly Phe Asp 1165 1170 1175 ccctac ttc gtc tac tcc ggc tcc atc ccc tac ctg gac ggc acc 18910 Pro TyrPhe Val Tyr Ser Gly Ser Ile Pro Tyr Leu Asp Gly Thr 1180 1185 1190 ttctac ctc aac cat act ttc aaa aag gtg tca atc atg ttc gac 18955 Phe TyrLeu Asn His Thr Phe Lys Lys Val Ser Ile Met Phe Asp 1195 1200 1205 tcctcc gtc agc tgg ccc ggc aac gac cgt ctg ctg acg ccc aac 19000 Ser SerVal Ser Trp Pro Gly Asn Asp Arg Leu Leu Thr Pro Asn 1210 1215 1220 gagttc gaa atc aag cgt tcg gtg gac ggt gaa ggg tac aac gtg 19045 Glu PheGlu Ile Lys Arg Ser Val Asp Gly Glu Gly Tyr Asn Val 1225 1230 1235 gctcag agc aac atg acc aag gac tgg ttc ctg att cag atg ctc 19090 Ala GlnSer Asn Met Thr Lys Asp Trp Phe Leu Ile Gln Met Leu 1240 1245 1250 agccac tac aac atc ggc tac cag ggc ttc tac gtg ccc gaa aat 19135 Ser HisTyr Asn Ile Gly Tyr Gln Gly Phe Tyr Val Pro Glu Asn 1255 1260 1265 tacaag gac cgc atg tac tct ttc ttc aga aac ttc caa ccc atg 19180 Tyr LysAsp Arg Met Tyr Ser Phe Phe Arg Asn Phe Gln Pro Met 1270 1275 1280 agccgc caa att gta gat tca acg gct tac act aat tat cag gat 19225 Ser ArgGln Ile Val Asp Ser Thr Ala Tyr Thr Asn Tyr Gln Asp 1285 1290 1295 gtgaaa ctg cca tac cag cat aac aac tca ggg ttc gtg ggc tac 19270 Val LysLeu Pro Tyr Gln His Asn Asn Ser Gly Phe Val Gly Tyr 1300 1305 1310 atggga ccc acc atg cga gag ggg cag gcc tac ccg gcc aac tat 19315 Met GlyPro Thr Met Arg Glu Gly Gln Ala Tyr Pro Ala Asn Tyr 1315 1320 1325 ccctat ccc ctg att ggg gcc acc gcc gtg ccc agc ctc acg cag 19360 Pro TyrPro Leu Ile Gly Ala Thr Ala Val Pro Ser Leu Thr Gln 1330 1335 1340 aaaaag ttc ctc tgc gac cgg gtg atg tgg agg atc ccc ttc tct 19405 Lys LysPhe Leu Cys Asp Arg Val Met Trp Arg Ile Pro Phe Ser 1345 1350 1355 agcaac ttc atg tct atg ggc tcc ctc acc gac ctg ggg cag aac 19450 Ser AsnPhe Met Ser Met Gly Ser Leu Thr Asp Leu Gly Gln Asn 1360 1365 1370 atgctg tac gcc aac tcc gct cac gcc ttg gat atg acc ttt gag 19495 Met LeuTyr Ala Asn Ser Ala His Ala Leu Asp Met Thr Phe Glu 1375 1380 1385 gtggat ccc atg gat gag ccc acg ctt ctc tat gtt ctg ttt gaa 19540 Val AspPro Met Asp Glu Pro Thr Leu Leu Tyr Val Leu Phe Glu 1390 1395 1400 gtcttc gac gtg gtg cgc atc cac cag ccg cac cgc ggc gtc atc 19585 Val PheAsp Val Val Arg Ile His Gln Pro His Arg Gly Val Ile 1405 1410 1415 gaggcc gtc tac ctg cgc aca cct ttc tct gcc ggt aac gcc acc 19630 Glu AlaVal Tyr Leu Arg Thr Pro Phe Ser Ala Gly Asn Ala Thr 1420 1425 1430 acctaa agaagccgat gggctccagc gaacaggagc tgcaggccat tgttcgcgac 19686 Thrctgggctgcg ggccctactt tttgggcacc ttcgacaagc gttttcccgg cttcatgtcc 19746ccccacaagc cggcctgtgc catcgttaac acggccggac gggagaccgg gggggtccac 19806tggctcgcct tcgcctggaa cccgcgtaac cgcacctgct acctgttcga cccttttggt 19866ttctccgacg aaaggctgaa gcagatctac cagttcgagt acgaggggct cctcaagcgc 19926agcgctctgg cctccacgcc cgaccactgc gtcaccctgg aaaagtccac ccaaacggtc 19986caggggcccc tctcggccgc ctgcgggctc ttctgttgca tgtttttgca cgccttcgtg 20046cactggcctc acacccccat ggatcacaac cccaccatgg atctgctcac cggagtgccc 20106aacagcatgc ttcacagccc ccaggtcgcc cccaccctgc gccgtaacca ggaacacctg 20166tatcgctttc tggggaaaca ctctgcctat tttcgccgcc accggcagcg catcgaacgg 20226gccacggcct tcgaaagcat gagccaaaga gtgtaatcaa taaaaaacat ttttatttga 20286catgatacgc gcttctggcg ttttattaaa aatcgaaggg ttcgagggag gggtcctcgt 20346gcccgctggg gagggacacg ttgcgatact ggaaacgggc gctccaacga aactcgggga 20406tcaccagccg cggcaggggc acgtcttcta ggttctgctt ccaaaactgc cgcaccagct 20466gcagggctcc catgacgtcg ggcgccgata tcttgaagtc gcagttaggg ccggagctcc 20526cgcggctgtt gcggaacacg gggttggcac actggaacac cagcacgccg gggttgtgga 20586tactggccag ggccgtcggg tcggtcacct ccgacgcatc cagatcctcg gcgttgctca 20646gggcaaacgg ggtcagcttg cacatctgcc gcccaatctg gggtactagg tcgcgcttgt 20706tgaggcagtc gcagcgcaga gggatcagga tgcgtcgctg cccgcgttgc atgatagggt 20766aactcgccgc caggaactcc tccatttgac ggaaggccat ctgggctttg ccgccctcgg 20826tgtagaatag cccgcaggac ttgctagaga atacgttatg accgcagttg acgtcctccg 20886cgcagcagcg ggcgtcttcg ttcttcagct gaaccacgtt gcggccccaa cggttctgga 20946ccaccttggc tctagtgggg tgctccttca gcgcccgctg tccgttctcg ctggttacat 21006ccatttccaa cacgtgctcc ttgcagacca tctccactcc gtggaagcaa aacaggacgc 21066cctcctgctg ggtactgcga tgctcccata cggcgcatcc ggtgggctcc cagctcttgt 21126gttttacccc cgcgtaggct tccatgtaag ccataaggaa tctgcccatc agctcggtga 21186aggtcttctg gttggtgaag gttagcggca ggccgcggtg ctcctcgttc aaccaagttt 21246gacagatctt gcggtacacc gctccctggt cgggcagaaa cttaaaagcc gctctgctgt 21306cgttgtctac gtggaacttc tccattaaca tcatcatggt ttccataccc ttctcccacg 21366ctgtcaccag tggtttgctg tcggggttct tcaccaacac ggcggtagag gggccctcgc 21426cggccccgac gtccttcatg gtcattcttt gaaactccac ggagccgtcc gcgcgacgta 21486ctctgcgcac cggagggtag ctgaagccca cctccaccac ggtgccttcg ccctcgctgt 21546cggagacaat ctccggggat ggcggcggcg cgggtgtcgc cttgcgagcc ttcttcttgg 21606gagggagctg aggcgcctcc tgctcgcgct cggggctcat ctcccgcaag tagggggtaa 21666tggagctgcc tgcttggttc tgacggttgg ccattgtatc ctaggcagaa agacatggag 21726cttatgcgcg aggaaacttt aaccgccccg tcccccgtca gcgacgaaga tgtcatcgtc 21786gaacaggacc cgggctacgt tacgccgccc gaggatctgg aggggcctga ccggcgcgac 21846gctagtgagc ggcaggaaaa tgagaaagag gaggcctgct acctcctgga aggcgacgtt 21906ttgctaaagc atttcgccag gcagagcacc atagttaagg aggccttgca agaccgctcc 21966gaggtgccct tggacgtcgc cgcgctctcc caggcctacg aggcgaacct tttctcgcct 22026cgagtgcctc cgaagagaca gcccaacggc acctgcgagc ccaacccgcg actcaacttc 22086taccccgtgt tcgccgtacc agaggcgctg gccacctatc acattttttt caaaaaccaa 22146cgcatccccc tatcgtgccg ggccaaccgc accgcggccg ataggaatct caggcttaaa 22206aacggagcca acatacctga tatcacgtcg ctggaggaag tgcccaagat tttcgagggt 22266ctgggtcgag atgagaagcg ggcggcgaac gctctgcaga aagaacagaa agagagtcag 22326aacgtgctgg tggagctgga gggggacaac gcgcgtctgg ccgtcctcaa acgctgcata 22386gaagtctccc acttcgccta ccccgccctc aacttgccac ccaaagttat gaaatcggtc 22446atggatcagc tgctcatcaa gagagctgag cccctggatc ccgaccaccc cgaggcggaa 22506aactcagagg acggaaagcc cgtcgtcagc gacgaggagc tcgagcggtg gctggaaacc 22566agggaccccc aacagttgca agagaggcgc aagatgatga tggcggccgt gctggtcacc 22626gtggagctgg aatgcctgca acggtttttc agcgacgtgg agacgctacg caaaatcggg 22686gaatccctgc actacacctt ccgccagggc tacgtccgcc aggcctgcaa gatctccaac 22746gtggagctca gcaacctggt ctcctacatg ggcatcctcc acgagaaccg gctggggcag 22806agcgtgctgc actgcacctt gcaaggcgag gcgcggcggg actacgtgcg agactgcatc 22866tacctcttcc tcaccctcac ctggcagacc gccatgggcg tctggcagca gtgcttggaa 22926gagagaaacc tcaaagagct agacaaactc ctctgccgcc agcggcgcgc cctgtggtcc 22986ggtttcagcg agcgcacggt cgccagcgct ctggcggaca tcatcttccc ggagcgcctg 23046atgaaaacct tgcaaaacgg cctgccggat ttcatcagtc aaagcatttt gcaaaacttc 23106cgctcttttg tcctggaacg ctccgggatc ttgcccgcca tgagctgcgc gctaccttct 23166gactttgtcc ccctctccta ccgcgagtgc cctcccccac tgtggagcca ctgctacctc 23226ttccaactgg ccaactttct ggcctaccac tccgacctca tggaagacgt aagcggagag 23286ggtttactgg agtgccactg ccgctgcaac ctgtgcaccc cccacagatc gctggcctgc 23346aacaccgagc tactcagcga aacccaggtc ataggtacct tcgagatcca ggggccccag 23406cagcaagagg gtgcttccgg cttgaagctc actccggcgc tgtggacctc ggcttactta 23466cgcaaatttg tagccgagga ctaccacgcc cacaaaattc agttttacga agaccaatct 23526cgaccaccga aagcccccct cacggcctgc gtcatcaccc agagcaagat cctggcccaa 23586ttgcaatcca tcaaccaagc gcgccgcgat ttccttttga aaaagggtcg gggggtgtac 23646ctggaccccc agaccggcga ggaactcaac ccgtccacac tctccgtcga agcagccccc 23706ccgagacatg ccgcccaagg gaaccgccaa gcagctgatc gctcggcaga gagcgaagaa 23766gcaagagctg ctccagcagc aggtggagga cgaggaagag atgtgggaca gccaggcaga 23826ggaggtgtca gaggacgagg aggagatgga aagctgggac agcctagacg aggaggagga 23886cgagctttca gaggaagagg cgaccgaaga aaaaccacct gcatccagcg cgccttctct 23946gagccgacag ccgaagcccc ggcccccgac gcccccggcc ggctcactca aagccagccg 24006taggtgggac gccaccgaat ctccagcggc agcggcaacg gcagcgggta aggccaaacg 24066cgagcggcgg gggtattgct cctggcgggc ccacaaaagc agtattgtga actgcttgca 24126acactgcggg ggaaacatct cctttgcccg acgctacctc ctcttccatc acggtgtggc 24186cttccctcgc aacgttctct attattaccg tcatctctac agcccctacg aaacgctcgg 24246agaaaaaagc taaggcctcc tccgccgcga ggaaaaactc cgccgccgct gccgccgcca 24306aggatccacc ggccaccgaa gagctgagaa agcgcatctt tcccactctg tatgctatct 24366ttcagcaaag ccgcgggcag caccctcagc gcgaactgaa aataaaaaac cgctccttcc 24426gctcgctcac ccgcagctgt ctgtaccaca agagagaaga ccagctgcag cgcaccctgg 24486acgacgccga agcactgttc agcaaatact gctcagcgtc tcttaaagac taaaagaccc 24546gcgctttttc cccctcggcc gccaaaaccc acgtcatcgc cagcatgagc aaggagattc 24606ccacccccta catgtggagc tatcagcccc agatgggcct ggccgcgggg gccgcccagg 24666actactccag caagatgaac tggctcagcg ccggccccca catgatctca cgagttaacg 24726gcatccgagc ccaccgaaac cagattctct tagaacaggc ggcaatcacc gccacacccc 24786ggcgccaact caacccgcct agttggcccg ccgcccaggt gtatcaggaa aatccccgcc 24846cgaccacagt cctcctgcca cgcgacgcgg aggccgaagt cctcatgact aactctgggg 24906tacaattagc gggcgggtcc aggtacgcca ggtacagagg tcgggccgct ccttactctc 24966ccgggagtat aaagagggtg atcattcgag gccgaggtat ccagctcaac gacgagacgg 25026tgagctcctc aaccggtctc agacctgacg gagtcttcca gctcggagga gcgggccgct 25086cttccttcac cactcgccag gcctacctga ccctgcagag ctcttcctcg cagccgcgct 25146ccgggggaat cggcactctc cagttcgtgg aagagttcgt tccctccgtc tacttcaacc 25206ccttctccgg ctcgcctgga cgctacccgg acgccttcat tcccaacttt gacgcagtga 25266gtgaatccgt ggacggctac gactgatgac agatggtgcg gccgtgagag ctcggctgcg 25326acatctgcat cactgccgtc agcctcgctg ctacgctcgg gaggcgatcg tcttcagcta 25386ctttgagctg ccggacgagc accctcaggg tccggctcac gggttgaaac tcgagatcga 25446gaacgcgctc gagtctcgcc tcatcgacac cttcaccgcc cgacctctcc tggtagaaat 25506ccaacggggg atcactacca tcaccctgtt ctgcatctgc cccacgcccg gattacatga 25566agatctgtgt tgtcatcttt gcgctcagtt taataaaaac tgaacttttt gccgcacctt 25626caacgccatc tgtgatttct acaacaaaaa gttcttctgg caaaggtaca caaactgtat 25686tttattctaa ttctacctca tctatcgtgc tgaactgcgc ctgcactaac gaacttatcc 25746agtggattgc aaacggtagt gtgtgcaagt acttttgggg gaacgatata gttagtagaa 25806ataacagcct ttgcgagcac tgcaactcct ccacactaat cctttatccc ccatttgtta 25866ctggatggta tatgtgcgtt ggctccggtt taaatcctag ttgctttcat aagtggtttc 25926tacaaaaaga gacccttccc aacaattctg tttctttttt cgccctatcc tactgctgtt 25986ctccctctgg ttactctttc aaacctctaa ttggtatttt agctttgata ctcataatct 26046ttattaactt tataataatt aacaacttac agtaaacatg cttgttctac tgctcgccac 26106atctttcgct ctctctcacg ccagaacaag tattgttggc gcaggttaca atgcaactct 26166tcaatctgct tacatgccag attccgacca gataccccat attacgtggt acttacaaac 26226ctccaaacct aattcttcat tttatgaagg aaacaaactc tgcgatgact ccgacaacag 26286aacgcacaca tttccccacc cttcactaca attcgaatgc gtaaacaaaa gcttgaagct 26346ttacaactta aagccttcag attctggctt gtaccatgct gtagttgaaa aaagtaattt 26406agaagtccac agtgattaca ttgaattgac ggttgtggac ctgccacctc caaaatgtga 26466ggtttcctcc tcttaccttg aagttcaagg cgtggatgcc tactgcctca tacacattaa 26526ctgcagcaac tctaaatatc cagctagaat ttactataat ggacaggaaa gtaatctttt 26586ttattattta acaacaagcg ctggtaacgg taaacagtta cctgactatt ttactgctgt 26646tgttgaattt tccacctaca gagaaacgta tgccaagcgg ccttacaatt tctcataccc 26706gtttaacgac ctttgcaatg aaatacaagc gctcgaaact ggaactgatt ttactccaat 26766tttcattgct gccattgttg taagcttaat taccattatt gtcagcctag cattttactg 26826cttttacaag cccaaaaacc ctaagtttga aaaacttaaa ctaaaacctg tcattcaaca 26886agtgtgattt tgttttccag catggtagct gcatttctac ttctcctctg tctacccatc 26946attttcgtct cttcaacttt cgccgcagtt tcccacctgg aaccagagtg cctaccgcct 27006tttgacgtgt atctgattct cacctttgtt tgttgtatat ccatttgcag tatagcctgc 27066ttttttataa caatctttca agccgccgac tatttttacg tgcgaattgc ttactttaga 27126caccatcctg aatacagaaa tcaaaacgtt gcctccttac tttgtttggc atgattaagt 27186tattgctgat acttaattat ttacccctaa tcaactgtaa ttgtccattc accaaaccct 27246ggtcattcta cacctgttat gataaaatcc ccgacactcc tgttgcttgg ctttacgcag 27306ccaccgccgc tttggtattt atatctactt gccttggagt aaaattgtat tttattttac 27366acactgggtg gctacatccc agagaagatt tacctagata tcctcttgta aacgcttttc 27426aattacagcc tctgcctcct cctgatcttc ttcctcgagc tccctctatt gtgagctact 27486ttcaactcac cggtggagat gactgactct caggacatta atattagtgt ggaaagaata 27546gctgctcagc gtcagcgaga aacgcgagtg ttggaatacc tggaactaca gcaacttaaa 27606gagtcccact ggtgtgagaa aggagtgctg tgccatgtta agcaggcagc cctttcctac 27666gatgtcagcg ttcagggaca tgaactgtct tacactttgc ctttgcagaa acaaaccttc 27726tgcaccatga tgggctctac ctccatcaca atcacccaac aagccgggcc tgtagagggg 27786gctatcctct gtcactgtca cgcacctgat tgcatgtcca aactaatcaa aactctctgt 27846gctttaggtg atatttttaa ggtgtaaatc aataataaac ttaccttaaa tttgacaaca 27906aatttctggt gacatcattc agcagcacca ctttaccctc ttcccagctc tcgtatggga 27966tgcgatagtg ggtggcaaac ttcctccaaa ccctaaaaga aatattggta tccacttcct 28026tgtcctcacc cacaattttc atcttttcat ag atg aaa aga acc aga gtt gat 28079Met Lys Arg Thr Arg Val Asp 1435 1440 gaa gac ttc aac ccc gtc tac ccctat gac acc aca acc act cct 28124 Glu Asp Phe Asn Pro Val Tyr Pro TyrAsp Thr Thr Thr Thr Pro 1445 1450 1455 gca gtt ccc ttt ata tca ccc cccttt gta aac agc gat ggt ctt 28169 Ala Val Pro Phe Ile Ser Pro Pro PheVal Asn Ser Asp Gly Leu 1460 1465 1470 cag gaa aac ccc cca ggt gtt ttaagt ctg cga ata gct aaa ccc 28214 Gln Glu Asn Pro Pro Gly Val Leu SerLeu Arg Ile Ala Lys Pro 1475 1480 1485 cta tat ttc gac atg gag aga aaacta gcc ctt tca ctt gga aga 28259 Leu Tyr Phe Asp Met Glu Arg Lys LeuAla Leu Ser Leu Gly Arg 1490 1495 1500 ggg ttg aca att acc gcc gcc ggacaa tta gaa agt acg cag agc 28304 Gly Leu Thr Ile Thr Ala Ala Gly GlnLeu Glu Ser Thr Gln Ser 1505 1510 1515 gta caa acc aac cca ccg ttg ataatt acc aac aac aac aca ctg 28349 Val Gln Thr Asn Pro Pro Leu Ile IleThr Asn Asn Asn Thr Leu 1520 1525 1530 acc cta cgt cat tct ccc ccc ttaaac cta act gac aat agc tta 28394 Thr Leu Arg His Ser Pro Pro Leu AsnLeu Thr Asp Asn Ser Leu 1535 1540 1545 gtg cta ggc tac tcg agt cct ctccgc gtc aca gac aac aaa ctt 28439 Val Leu Gly Tyr Ser Ser Pro Leu ArgVal Thr Asp Asn Lys Leu 1550 1555 1560 aca ttt aac ttc aca tca cca ctccgt tat gaa aat gaa aac ctt 28484 Thr Phe Asn Phe Thr Ser Pro Leu ArgTyr Glu Asn Glu Asn Leu 1565 1570 1575 act ttt aac tat aca gag cct cttaaa ctt ata aat aac agc ctt 28529 Thr Phe Asn Tyr Thr Glu Pro Leu LysLeu Ile Asn Asn Ser Leu 1580 1585 1590 gcc att gac atc aat tcc tca aaaggc ctt agt agc gtc gga ggc 28574 Ala Ile Asp Ile Asn Ser Ser Lys GlyLeu Ser Ser Val Gly Gly 1595 1600 1605 tca cta gct gta aac ctg agt tcagac tta aag ttt gac agc aac 28619 Ser Leu Ala Val Asn Leu Ser Ser AspLeu Lys Phe Asp Ser Asn 1610 1615 1620 gga tcc ata gct ttt ggc ata caaacc ctg tgg acc gct ccg acc 28664 Gly Ser Ile Ala Phe Gly Ile Gln ThrLeu Trp Thr Ala Pro Thr 1625 1630 1635 tcg act ggc aac tgc acc gtc tacagc gag ggc gat tcc cta ctt 28709 Ser Thr Gly Asn Cys Thr Val Tyr SerGlu Gly Asp Ser Leu Leu 1640 1645 1650 agt ctc tgt tta acc aaa tgc ggagct cac gtc tta gga agt gta 28754 Ser Leu Cys Leu Thr Lys Cys Gly AlaHis Val Leu Gly Ser Val 1655 1660 1665 agt tta acc ggt tta aca gga accata acc caa atg act gat att 28799 Ser Leu Thr Gly Leu Thr Gly Thr IleThr Gln Met Thr Asp Ile 1670 1675 1680 tct gtc acc att caa ttt aca tttgac aac aat ggt aag cta cta 28844 Ser Val Thr Ile Gln Phe Thr Phe AspAsn Asn Gly Lys Leu Leu 1685 1690 1695 agc tct cca ctt ata aac aac gccttt agt att cga cag aat gac 28889 Ser Ser Pro Leu Ile Asn Asn Ala PheSer Ile Arg Gln Asn Asp 1700 1705 1710 agt acg gcc tca aac cct acc tacaac gcc ctg gcg ttt atg cct 28934 Ser Thr Ala Ser Asn Pro Thr Tyr AsnAla Leu Ala Phe Met Pro 1715 1720 1725 aac agt acc ata tat gca aga ggggga ggt ggt gaa cca cga aac 28979 Asn Ser Thr Ile Tyr Ala Arg Gly GlyGly Gly Glu Pro Arg Asn 1730 1735 1740 aac tac tac gtc caa acg tat cttagg gga aat gtt caa aaa cca 29024 Asn Tyr Tyr Val Gln Thr Tyr Leu ArgGly Asn Val Gln Lys Pro 1745 1750 1755 atc att ctt act gta acc tac aactca gtc gcc aca gga tat tcc 29069 Ile Ile Leu Thr Val Thr Tyr Asn SerVal Ala Thr Gly Tyr Ser 1760 1765 1770 tta tct ttt aag tgg act gct cttgca cgt gaa aag ttt gca acc 29114 Leu Ser Phe Lys Trp Thr Ala Leu AlaArg Glu Lys Phe Ala Thr 1775 1780 1785 cca aca acc tcg ttt tgc tac attaca gaa caa taa aaccgtgtac 29160 Pro Thr Thr Ser Phe Cys Tyr Ile Thr GluGln 1790 1795 cccaccgttt cgtttttttc ag atg aaa cgg gcg aga gtt gat gaagac 29209 Met Lys Arg Ala Arg Val Asp Glu Asp 1800 1805 ttc aac cca gtgtac cct tat gac ccc cca cat gct cct gtt atg 29254 Phe Asn Pro Val TyrPro Tyr Asp Pro Pro His Ala Pro Val Met 1810 1815 1820 ccc ttc att actcca cct ttt acc tcc tcg gat ggg ttg cag gaa 29299 Pro Phe Ile Thr ProPro Phe Thr Ser Ser Asp Gly Leu Gln Glu 1825 1830 1835 aaa cca ctt ggagtg tta agt tta aac tac aga gat ccc att act 29344 Lys Pro Leu Gly ValLeu Ser Leu Asn Tyr Arg Asp Pro Ile Thr 1840 1845 1850 acg caa aat gagtct ctt aca att aaa cta gga aac ggc ctc act 29389 Thr Gln Asn Glu SerLeu Thr Ile Lys Leu Gly Asn Gly Leu Thr 1855 1860 1865 cta gac aac caggga caa cta aca tca acc gct ggc gaa gta gaa 29434 Leu Asp Asn Gln GlyGln Leu Thr Ser Thr Ala Gly Glu Val Glu 1870 1875 1880 cct cca ctc actaac gct aac aac aaa ctt gca ctg gtc tat agc 29479 Pro Pro Leu Thr AsnAla Asn Asn Lys Leu Ala Leu Val Tyr Ser 1885 1890 1895 gat cct tta gcagta aag cgc aac agc cta acc tta tcg cac acc 29524 Asp Pro Leu Ala ValLys Arg Asn Ser Leu Thr Leu Ser His Thr 1900 1905 1910 gct ccc ctt gttatt gct gat aac tct tta gca ttg caa gtt tca 29569 Ala Pro Leu Val IleAla Asp Asn Ser Leu Ala Leu Gln Val Ser 1915 1920 1925 gag cct att tttata aat gac aag gac aaa cta gcc ctg caa aca 29614 Glu Pro Ile Phe IleAsn Asp Lys Asp Lys Leu Ala Leu Gln Thr 1930 1935 1940 gcc gcg ccc cttgta act aac gct ggc acc ctt cgc tta caa agc 29659 Ala Ala Pro Leu ValThr Asn Ala Gly Thr Leu Arg Leu Gln Ser 1945 1950 1955 gcc gcc cct ttaggc att gca gac caa acc cta aaa ctc ctg ttt 29704 Ala Ala Pro Leu GlyIle Ala Asp Gln Thr Leu Lys Leu Leu Phe 1960 1965 1970 acc aac cct ttgtac ttg cag aat aac ttt ctc acg tta gcc att 29749 Thr Asn Pro Leu TyrLeu Gln Asn Asn Phe Leu Thr Leu Ala Ile 1975 1980 1985 gaa cga ccc cttgcc att acc aat act gga aag ctg gct cta cag 29794 Glu Arg Pro Leu AlaIle Thr Asn Thr Gly Lys Leu Ala Leu Gln 1990 1995 2000 ctc tcc cca ccgcta caa aca gca gac aca ggc ttg act ttg caa 29839 Leu Ser Pro Pro LeuGln Thr Ala Asp Thr Gly Leu Thr Leu Gln 2005 2010 2015 acc aac gtg ccatta act gta agc aac ggg acc cta ggc tta gcc 29884 Thr Asn Val Pro LeuThr Val Ser Asn Gly Thr Leu Gly Leu Ala 2020 2025 2030 ata aag cgc ccactt att att cag gac aac aac ttg ttt ttg gac 29929 Ile Lys Arg Pro LeuIle Ile Gln Asp Asn Asn Leu Phe Leu Asp 2035 2040 2045 ttc aga gct cccctg cgt ctt ttc aac agc gac cca gta cta ggg 29974 Phe Arg Ala Pro LeuArg Leu Phe Asn Ser Asp Pro Val Leu Gly 2050 2055 2060 ctt aac ttt tacacc cct ctt gcg gta cgc gat gag gcg ctc act 30019 Leu Asn Phe Tyr ThrPro Leu Ala Val Arg Asp Glu Ala Leu Thr 2065 2070 2075 gtt aac aca ggccgc ggc ctc aca gtg agt tac gat ggt tta att 30064 Val Asn Thr Gly ArgGly Leu Thr Val Ser Tyr Asp Gly Leu Ile 2080 2085 2090 tta aat ctt ggtaag gat ctt cgc ttt gac aac aac acc gtt tct 30109 Leu Asn Leu Gly LysAsp Leu Arg Phe Asp Asn Asn Thr Val Ser 2095 2100 2105 gtc gct ctt agtgct gct ttg cct tta caa tac act gat cag ctt 30154 Val Ala Leu Ser AlaAla Leu Pro Leu Gln Tyr Thr Asp Gln Leu 2110 2115 2120 cgc ctt aac gtgggc gct ggg ctg cgt tac aat cca gtg agt aag 30199 Arg Leu Asn Val GlyAla Gly Leu Arg Tyr Asn Pro Val Ser Lys 2125 2130 2135 aaa ttg gac gtgaac ccc aat caa aac aag ggt tta acc tgg gaa 30244 Lys Leu Asp Val AsnPro Asn Gln Asn Lys Gly Leu Thr Trp Glu 2140 2145 2150 aat gac tac ctcatt gta aag cta gga aat gga tta ggt ttt gat 30289 Asn Asp Tyr Leu IleVal Lys Leu Gly Asn Gly Leu Gly Phe Asp 2155 2160 2165 ggc gat gga aacata gct gtt tct cct caa gtt aca tcg cct gac 30334 Gly Asp Gly Asn IleAla Val Ser Pro Gln Val Thr Ser Pro Asp 2170 2175 2180 acc tta tgg accact gcc gac cca tcc ccc aat tgt tcc atc tac 30379 Thr Leu Trp Thr ThrAla Asp Pro Ser Pro Asn Cys Ser Ile Tyr 2185 2190 2195 act gat tta gatgcc aaa atg tgg ctc tcg ttg gta aaa caa ggg 30424 Thr Asp Leu Asp AlaLys Met Trp Leu Ser Leu Val Lys Gln Gly 2200 2205 2210 ggt gtg gtt cacggt tct gtt gct tta aaa gca ttg aaa gga acc 30469 Gly Val Val His GlySer Val Ala Leu Lys Ala Leu Lys Gly Thr 2215 2220 2225 cta ttg agt cctacg gaa agc gcc att gtt att ata cta cat ttt 30514 Leu Leu Ser Pro ThrGlu Ser Ala Ile Val Ile Ile Leu His Phe 2230 2235 2240 gac aat tat ggagtg cga att ctc aat tat ccc act ttg ggc act 30559 Asp Asn Tyr Gly ValArg Ile Leu Asn Tyr Pro Thr Leu Gly Thr 2245 2250 2255 caa ggc acg ttggga aat aat gca act tgg ggt tat agg cag gga 30604 Gln Gly Thr Leu GlyAsn Asn Ala Thr Trp Gly Tyr Arg Gln Gly 2260 2265 2270 gaa tct gca gacact aat gta ctc aat gca cta gca ttt atg ccc 30649 Glu Ser Ala Asp ThrAsn Val Leu Asn Ala Leu Ala Phe Met Pro 2275 2280 2285 agt tca aaa aggtac cca aga ggg cgt gga agc gaa gtt cag aat 30694 Ser Ser Lys Arg TyrPro Arg Gly Arg Gly Ser Glu Val Gln Asn 2290 2295 2300 caa act gtg ggctac act tgt ata cag ggt gac ttt tct atg ccc 30739 Gln Thr Val Gly TyrThr Cys Ile Gln Gly Asp Phe Ser Met Pro 2305 2310 2315 gta ccg tac caaata cag tac aac tat gga cca act ggc tac tcc 30784 Val Pro Tyr Gln IleGln Tyr Asn Tyr Gly Pro Thr Gly Tyr Ser 2320 2325 2330 ttt aaa ttt atttgg aga act gtt tca aga caa cca ttt gac atc 30829 Phe Lys Phe Ile TrpArg Thr Val Ser Arg Gln Pro Phe Asp Ile 2335 2340 2345 cca tgc tgt tttttc tct tac att acg gaa gaa taa aacaactttt 30875 Pro Cys Cys Phe Phe SerTyr Ile Thr Glu Glu 2350 2355 tctttttatt ttctttttat tttacacgcacagtaaggct tcctccaccc ttccatctca 30935 cagcatacac cagcctctcc cccttcatggcagtaaactg ttgtgagtca gtccggtatt 30995 tgggagttaa gatccaaaca gtctctttggtgatgaaaca tggatccgtg atggacacaa 31055 atccctggga caggttctcc aacgtttcggtaaaaaactg catgccgccc tacaaaacaa 31115 acaggttcag gctctccacg ggttatctccccgatcaaac tcagacagag taaaggtgcg 31175 atgatgttcc actaaaccac gcaggtggcgctgtctgaac ctctcggtgc gactcctgtg 31235 aggctggtaa gaagttagat tgtccagcagcctcacagca tggatcatca gtctacgagt 31295 gcgtctggcg cagcagcgca tctgaatctcactgagattc cggcaagaat cgcacaccat 31355 cacaatcagg ttgttcatga tcccatagctgaacacgctc cagccaaagc tcattcgctc 31415 caacagcgcc accgcgtgtc cgtccaaccttactttaaca taaatcaggt gtctgccgcg 31475 tacaaacatg ctacccgcat acagaacctcccggggcaaa cccctgttca ccacctgcct 31535 gtaccaggga aacctcacat ttatcagggagccatagata gccattttaa accaattagc 31595 taacaccgcc ccaccagctc tacactgaagagaaccggga gagttacaat gacagtgaat 31655 aatccatctc tcataacccc taatggtctgatggaaatcc agatctaacg tggcacagca 31715 gatacacact ttcatataca ttttcatcacatgtttttcc caggccgtta aaatacaatc 31775 ccaatacacg ggccactcct gcagtacaataaagctaata caagatggta tactcctcac 31835 ctcactaaca ttgtgcatgt tcatattttcacattctaag taccgagagt tctcctctac 31895 aacagcactg ccgcggtcct cacaaggtggtagctggtga cgattgtaag gagccagtct 31955 gcagcgatac cgtctgtcgc gttgcatcgtagaccaggga ccgacgcact tcctcgtact 32015 tgtagtagca gaaccacgtc cgctgccagcacgtctccaa gtaacgccgg tccctgcgtc 32075 gctcacgctc cctcctcaac gcaaagtgcaaccactcttg taatccacac agatccctct 32135 cggcctccgg ggcgatgcac acctcaaacctacagatgtc tcggtacagt tccaaacacg 32195 tagtgagggc gagttccaac caagacagacagcctgatct atcccgacac actggaggtg 32255 gaggaagaca cggaagaggc atgttattccaagcgattca ccaacgggtc gaaatgaaga 32315 tcccgaagat gacaacggtc gcctccggagccctgatgga atttaacagc cagatcaaac 32375 attatgcgat tttccaggct atcaatcgcggcctccaaaa gagcctggac ccgcacttcc 32435 acaaacacca gcaaagcaaa agcgttattatcaaactctt cgatcatcaa gctgcaggac 32495 tgtacaatgc ccaagtaatt ttcatttctccactcgcgaa tgatgtcgcg gcaaatagtc 32555 tgaaggttca tgccgtgcat attaaaaagctccgaaaggg cgccctctat agccatgcgt 32615 agacacacca tcatgactgc aagatatcgggctcctgaga cacctgcagc agatttaaca 32675 gacccaggtc aggttgctct ccgcgatcgcgaatctccat ccgcaaagtc atttgcaaat 32735 aattaaatag atctgcgccg actaaatctgttaactccgc gctaggaact aaatcaggtg 32795 tggctacgca gcacaaaagt tccagggatggcgccaaact cactagaacc gctcccgagt 32855 agcaaaactg atgaatggga gtaacacagtgtaaaatgtt cagccaaaaa tcactaagct 32915 gctcctttaa aaagtccagt acttctatattcagttcgtg caagtactga agcaactgtg 32975 cgggaatatg cacagcaaaa aaaatagggcggctcagata catgttgacc taaaataaaa 33035 agaatcatta aactaaagaa gcctggcgaacggtgggata tatgacacgc tccagcagca 33095 ggcaagcaac cggctgtccc cgggaaccgcggtaaaattc atccgaatga ttaaaaagaa 33155 caacagagac ttcccaccat gtactcggttggatctcctg agcacagagc aatacccccc 33215 tcacattcat atccgctaca gaaaaaaaacgtcccagata cccagcggga atatccaacg 33275 acagctgcaa agacagcaaa acaatccctctgggagcaat cacaaaatcc tccggtgaaa 33335 aaagcacata catattagaa taaccctgttgctggggcaa aaaggcccgt cgtcccagca 33395 aatgcacata aatatgttca tcagccattgccccgtctta ccgcgtaaac agccacgaaa 33455 aaatcgagct aaaatccacc caacagcctatagctatata tacactccac ccaatgacgc 33515 taataccgca ccacccacga ccaaagttcacccacaccca caaaacccgc gaaaatccag 33575 cgccgtcagc acttccgcaa tttcagtctcacaacgtcac ttccgcgcgc cttttcactt 33635 tcccacacac gcccttcgcc cgcccgccctcgcgccaccc cgcgtcaccc cacgtcaccg 33695 cacgtcaccc cggccccgcc tcgctcctccccgctcatta tcatattggc acgtttccag 33755 aataaggtat attattgatg cagcaaaacaatccctctgg gagcaatcac aaaatcctcc 33815 ggtgaaaaaa gcacatacat attagaataaccctgttgct ggggcaaaaa ggcccgtcgt 33875 cccagcaaat gcacataaat atgttcatcagccattgccc cgtcttaccg cgtaaacagc 33935 cacgaaaaaa tcgagctaaa atccacccaacagcctatag ctatatatac actccaccca 33995 atgacgctaa taccgcacca cccacgaccaaagttcaccc acacccacaa aacccgcgaa 34055 aatccagcgc cgtcagcact tccgcaatttcagtctcaca acgtcacttc cgcgcgcctt 34115 ttcactttcc cacacacgcc cttcgcccgcccgccctcgc gccaccccgc gtcaccccac 34175 gtcaccgcac gtcaccccgg ccccgcctcgctcctccccg ctcattatca tattggcacg 34235 tttccagaat aaggtatatt attgatgca34264 25 503 PRT simian adenovirus SV-1 25 Met Arg Arg Ala Val Arg ValThr Pro Ala Ala Tyr Glu Gly Pro Pro 1 5 10 15 Pro Ser Tyr Glu Ser ValMet Gly Ser Ala Asn Val Pro Ala Thr Leu 20 25 30 Glu Ala Pro Tyr Val ProPro Arg Tyr Leu Gly Pro Thr Glu Gly Arg 35 40 45 Asn Ser Ile Arg Tyr SerGlu Leu Ala Pro Leu Tyr Asp Thr Thr Lys 50 55 60 Val Tyr Leu Val Asp AsnLys Ser Ala Asp Ile Ala Ser Leu Asn Tyr 65 70 75 80 Gln Asn Asp His SerAsn Phe Leu Thr Thr Val Val Gln Asn Asn Asp 85 90 95 Phe Thr Pro Thr GluAla Gly Thr Gln Thr Ile Asn Phe Asp Glu Arg 100 105 110 Ser Arg Trp GlyGly Gln Leu Lys Thr Ile Leu His Thr Asn Met Pro 115 120 125 Asn Ile AsnGlu Phe Met Ser Thr Asn Lys Phe Arg Ala Arg Leu Met 130 135 140 Val LysLys Ala Glu Asn Gln Pro Pro Glu Tyr Glu Trp Phe Glu Phe 145 150 155 160Thr Ile Pro Glu Gly Asn Tyr Ser Glu Thr Met Thr Ile Asp Leu Met 165 170175 Asn Asn Ala Ile Val Asp Asn Tyr Leu Gln Val Gly Arg Gln Asn Gly 180185 190 Val Leu Glu Ser Asp Ile Gly Val Lys Phe Asp Thr Arg Asn Phe Arg195 200 205 Leu Gly Trp Asp Pro Val Thr Lys Leu Val Met Pro Gly Val TyrThr 210 215 220 Asn Glu Ala Phe His Pro Asp Ile Val Leu Leu Pro Gly CysGly Val 225 230 235 240 Asp Phe Thr Gln Ser Arg Leu Ser Asn Leu Leu GlyIle Arg Lys Arg 245 250 255 Arg Pro Phe Gln Glu Gly Phe Gln Ile Met TyrGlu Asp Leu Glu Gly 260 265 270 Gly Asn Ile Pro Gly Leu Leu Asp Val ProAla Tyr Glu Glu Ser Val 275 280 285 Lys Gln Ala Glu Ala Gln Gly Arg GluIle Arg Gly Asp Thr Phe Ala 290 295 300 Thr Glu Pro His Glu Leu Val IleLys Pro Leu Glu Gln Asp Ser Lys 305 310 315 320 Lys Arg Ser Tyr Asn IleIle Ser Gly Thr Met Asn Thr Leu Tyr Arg 325 330 335 Ser Trp Phe Leu AlaTyr Asn Tyr Gly Asp Pro Glu Lys Gly Val Arg 340 345 350 Ser Trp Thr IleLeu Thr Thr Thr Asp Val Thr Cys Gly Ser Gln Gln 355 360 365 Val Tyr TrpSer Leu Pro Asp Met Met Gln Asp Pro Val Thr Phe Arg 370 375 380 Pro SerThr Gln Val Ser Asn Phe Pro Val Val Gly Thr Glu Leu Leu 385 390 395 400Pro Val His Ala Lys Ser Phe Tyr Asn Glu Gln Ala Val Tyr Ser Gln 405 410415 Leu Ile Arg Gln Ser Thr Ala Leu Thr His Val Phe Asn Arg Phe Pro 420425 430 Glu Asn Gln Ile Leu Val Arg Pro Pro Ala Pro Thr Ile Thr Thr Val435 440 445 Ser Glu Asn Val Pro Ala Leu Thr Asp His Gly Thr Leu Pro LeuArg 450 455 460 Ser Ser Ile Ser Gly Val Gln Arg Val Thr Ile Thr Asp AlaArg Arg 465 470 475 480 Arg Thr Cys Pro Tyr Val Tyr Lys Ala Leu Gly ValVal Ala Pro Lys 485 490 495 Val Leu Ser Ser Arg Thr Phe 500 26 931 PRTsimian adenovirus SV-1 26 Met Ala Thr Pro Ser Met Met Pro Gln Trp SerTyr Met His Ile Ala 1 5 10 15 Gly Gln Asp Ala Ser Glu Tyr Leu Ser ProGly Leu Val Gln Phe Ala 20 25 30 Arg Ala Thr Asp Thr Tyr Phe Ser Leu GlyAsn Lys Phe Arg Asn Pro 35 40 45 Thr Val Ala Pro Thr His Asp Val Thr ThrAsp Arg Ser Gln Arg Leu 50 55 60 Thr Leu Arg Phe Val Pro Val Asp Arg GluAsp Thr Ala Tyr Ser Tyr 65 70 75 80 Lys Val Arg Tyr Thr Leu Ala Val GlyAsp Asn Arg Val Leu Asp Met 85 90 95 Ala Ser Thr Tyr Phe Asp Ile Arg GlyVal Leu Asp Arg Gly Pro Ser 100 105 110 Phe Lys Pro Tyr Ser Gly Thr AlaTyr Asn Ser Leu Ala Pro Lys Gly 115 120 125 Ala Pro Asn Pro Ala Glu TrpThr Asn Ser Asp Ser Lys Val Lys Val 130 135 140 Arg Ala Gln Ala Pro PheVal Ser Ser Tyr Gly Ala Thr Ala Ile Thr 145 150 155 160 Lys Glu Gly IleGln Val Gly Val Thr Leu Thr Asp Ser Gly Ser Thr 165 170 175 Pro Gln TyrAla Asp Lys Thr Tyr Gln Pro Glu Pro Gln Ile Gly Glu 180 185 190 Leu GlnTrp Asn Ser Asp Val Gly Thr Asp Asp Lys Ile Ala Gly Arg 195 200 205 ValLeu Lys Lys Thr Thr Pro Met Phe Pro Cys Tyr Gly Ser Tyr Ala 210 215 220Arg Pro Thr Asn Glu Lys Gly Gly Gln Ala Thr Pro Ser Ala Ser Gln 225 230235 240 Asp Val Gln Asn Pro Glu Leu Gln Phe Phe Ala Ser Thr Asn Val Ala245 250 255 Asn Thr Pro Lys Ala Val Leu Tyr Ala Glu Asp Val Ser Ile GluAla 260 265 270 Pro Asp Thr His Leu Val Phe Lys Pro Thr Val Thr Glu GlyIle Thr 275 280 285 Ser Ser Glu Ala Leu Leu Thr Gln Gln Ala Ala Pro AsnArg Pro Asn 290 295 300 Tyr Ile Ala Phe Arg Asp Asn Phe Ile Gly Leu MetTyr Tyr Asn Ser 305 310 315 320 Thr Gly Asn Met Gly Val Leu Ala Gly GlnAla Ser Gln Leu Asn Ala 325 330 335 Val Val Asp Leu Gln Asp Arg Asn ThrGlu Leu Ser Tyr Gln Leu Met 340 345 350 Leu Asp Ala Leu Gly Asp Arg SerArg Tyr Phe Ser Met Trp Asn Gln 355 360 365 Ala Val Asp Ser Tyr Asp ProAsp Val Arg Ile Ile Glu Asn His Gly 370 375 380 Val Glu Asp Glu Leu ProAsn Tyr Cys Phe Pro Leu Gly Gly Met Ala 385 390 395 400 Val Thr Asp ThrTyr Ser Pro Ile Lys Val Asn Gly Gly Gly Asn Gly 405 410 415 Trp Glu AlaAsn Asn Gly Val Phe Thr Glu Arg Gly Val Glu Ile Gly 420 425 430 Ser GlyAsn Met Phe Ala Met Glu Ile Asn Leu Gln Ala Asn Leu Trp 435 440 445 ArgSer Phe Leu Tyr Ser Asn Ile Gly Leu Tyr Leu Pro Asp Ser Leu 450 455 460Lys Ile Thr Pro Asp Asn Ile Thr Leu Pro Glu Asn Lys Asn Thr Tyr 465 470475 480 Gln Tyr Met Asn Gly Arg Val Thr Pro Pro Gly Leu Val Asp Thr Tyr485 490 495 Val Asn Val Gly Ala Arg Trp Ser Pro Asp Val Met Asp Ser IleAsn 500 505 510 Pro Phe Asn His His Arg Asn Ala Gly Leu Arg Tyr Arg SerMet Leu 515 520 525 Leu Gly Asn Gly Arg Tyr Val Pro Phe His Ile Gln ValPro Gln Lys 530 535 540 Phe Phe Ala Ile Lys Asn Leu Leu Leu Leu Pro GlySer Tyr Thr Tyr 545 550 555 560 Glu Trp Asn Phe Arg Lys Asp Val Asn MetIle Leu Gln Ser Ser Leu 565 570 575 Gly Asn Asp Leu Arg Val Asp Gly AlaSer Ile Arg Phe Asp Ser Ile 580 585 590 Asn Leu Tyr Ala Asn Phe Phe ProMet Ala His Asn Thr Ala Ser Thr 595 600 605 Leu Glu Ala Met Leu Arg AsnAsp Thr Asn Asp Gln Ser Phe Asn Asp 610 615 620 Tyr Leu Cys Ala Ala AsnMet Leu Tyr Pro Ile Pro Ala Asn Ala Thr 625 630 635 640 Ser Val Pro IleSer Ile Pro Ser Arg Asn Trp Ala Ala Phe Arg Gly 645 650 655 Trp Ser PheThr Arg Leu Lys Thr Lys Glu Thr Pro Ser Leu Gly Ser 660 665 670 Gly PheAsp Pro Tyr Phe Val Tyr Ser Gly Ser Ile Pro Tyr Leu Asp 675 680 685 GlyThr Phe Tyr Leu Asn His Thr Phe Lys Lys Val Ser Ile Met Phe 690 695 700Asp Ser Ser Val Ser Trp Pro Gly Asn Asp Arg Leu Leu Thr Pro Asn 705 710715 720 Glu Phe Glu Ile Lys Arg Ser Val Asp Gly Glu Gly Tyr Asn Val Ala725 730 735 Gln Ser Asn Met Thr Lys Asp Trp Phe Leu Ile Gln Met Leu SerHis 740 745 750 Tyr Asn Ile Gly Tyr Gln Gly Phe Tyr Val Pro Glu Asn TyrLys Asp 755 760 765 Arg Met Tyr Ser Phe Phe Arg Asn Phe Gln Pro Met SerArg Gln Ile 770 775 780 Val Asp Ser Thr Ala Tyr Thr Asn Tyr Gln Asp ValLys Leu Pro Tyr 785 790 795 800 Gln His Asn Asn Ser Gly Phe Val Gly TyrMet Gly Pro Thr Met Arg 805 810 815 Glu Gly Gln Ala Tyr Pro Ala Asn TyrPro Tyr Pro Leu Ile Gly Ala 820 825 830 Thr Ala Val Pro Ser Leu Thr GlnLys Lys Phe Leu Cys Asp Arg Val 835 840 845 Met Trp Arg Ile Pro Phe SerSer Asn Phe Met Ser Met Gly Ser Leu 850 855 860 Thr Asp Leu Gly Gln AsnMet Leu Tyr Ala Asn Ser Ala His Ala Leu 865 870 875 880 Asp Met Thr PheGlu Val Asp Pro Met Asp Glu Pro Thr Leu Leu Tyr 885 890 895 Val Leu PheGlu Val Phe Asp Val Val Arg Ile His Gln Pro His Arg 900 905 910 Gly ValIle Glu Ala Val Tyr Leu Arg Thr Pro Phe Ser Ala Gly Asn 915 920 925 AlaThr Thr 930 27 363 PRT simian adenovirus SV-1 27 Met Lys Arg Thr Arg ValAsp Glu Asp Phe Asn Pro Val Tyr Pro Tyr 1 5 10 15 Asp Thr Thr Thr ThrPro Ala Val Pro Phe Ile Ser Pro Pro Phe Val 20 25 30 Asn Ser Asp Gly LeuGln Glu Asn Pro Pro Gly Val Leu Ser Leu Arg 35 40 45 Ile Ala Lys Pro LeuTyr Phe Asp Met Glu Arg Lys Leu Ala Leu Ser 50 55 60 Leu Gly Arg Gly LeuThr Ile Thr Ala Ala Gly Gln Leu Glu Ser Thr 65 70 75 80 Gln Ser Val GlnThr Asn Pro Pro Leu Ile Ile Thr Asn Asn Asn Thr 85 90 95 Leu Thr Leu ArgHis Ser Pro Pro Leu Asn Leu Thr Asp Asn Ser Leu 100 105 110 Val Leu GlyTyr Ser Ser Pro Leu Arg Val Thr Asp Asn Lys Leu Thr 115 120 125 Phe AsnPhe Thr Ser Pro Leu Arg Tyr Glu Asn Glu Asn Leu Thr Phe 130 135 140 AsnTyr Thr Glu Pro Leu Lys Leu Ile Asn Asn Ser Leu Ala Ile Asp 145 150 155160 Ile Asn Ser Ser Lys Gly Leu Ser Ser Val Gly Gly Ser Leu Ala Val 165170 175 Asn Leu Ser Ser Asp Leu Lys Phe Asp Ser Asn Gly Ser Ile Ala Phe180 185 190 Gly Ile Gln Thr Leu Trp Thr Ala Pro Thr Ser Thr Gly Asn CysThr 195 200 205 Val Tyr Ser Glu Gly Asp Ser Leu Leu Ser Leu Cys Leu ThrLys Cys 210 215 220 Gly Ala His Val Leu Gly Ser Val Ser Leu Thr Gly LeuThr Gly Thr 225 230 235 240 Ile Thr Gln Met Thr Asp Ile Ser Val Thr IleGln Phe Thr Phe Asp 245 250 255 Asn Asn Gly Lys Leu Leu Ser Ser Pro LeuIle Asn Asn Ala Phe Ser 260 265 270 Ile Arg Gln Asn Asp Ser Thr Ala SerAsn Pro Thr Tyr Asn Ala Leu 275 280 285 Ala Phe Met Pro Asn Ser Thr IleTyr Ala Arg Gly Gly Gly Gly Glu 290 295 300 Pro Arg Asn Asn Tyr Tyr ValGln Thr Tyr Leu Arg Gly Asn Val Gln 305 310 315 320 Lys Pro Ile Ile LeuThr Val Thr Tyr Asn Ser Val Ala Thr Gly Tyr 325 330 335 Ser Leu Ser PheLys Trp Thr Ala Leu Ala Arg Glu Lys Phe Ala Thr 340 345 350 Pro Thr ThrSer Phe Cys Tyr Ile Thr Glu Gln 355 360 28 560 PRT simian adenovirusSV-1 28 Met Lys Arg Ala Arg Val Asp Glu Asp Phe Asn Pro Val Tyr Pro Tyr1 5 10 15 Asp Pro Pro His Ala Pro Val Met Pro Phe Ile Thr Pro Pro PheThr 20 25 30 Ser Ser Asp Gly Leu Gln Glu Lys Pro Leu Gly Val Leu Ser LeuAsn 35 40 45 Tyr Arg Asp Pro Ile Thr Thr Gln Asn Glu Ser Leu Thr Ile LysLeu 50 55 60 Gly Asn Gly Leu Thr Leu Asp Asn Gln Gly Gln Leu Thr Ser ThrAla 65 70 75 80 Gly Glu Val Glu Pro Pro Leu Thr Asn Ala Asn Asn Lys LeuAla Leu 85 90 95 Val Tyr Ser Asp Pro Leu Ala Val Lys Arg Asn Ser Leu ThrLeu Ser 100 105 110 His Thr Ala Pro Leu Val Ile Ala Asp Asn Ser Leu AlaLeu Gln Val 115 120 125 Ser Glu Pro Ile Phe Ile Asn Asp Lys Asp Lys LeuAla Leu Gln Thr 130 135 140 Ala Ala Pro Leu Val Thr Asn Ala Gly Thr LeuArg Leu Gln Ser Ala 145 150 155 160 Ala Pro Leu Gly Ile Ala Asp Gln ThrLeu Lys Leu Leu Phe Thr Asn 165 170 175 Pro Leu Tyr Leu Gln Asn Asn PheLeu Thr Leu Ala Ile Glu Arg Pro 180 185 190 Leu Ala Ile Thr Asn Thr GlyLys Leu Ala Leu Gln Leu Ser Pro Pro 195 200 205 Leu Gln Thr Ala Asp ThrGly Leu Thr Leu Gln Thr Asn Val Pro Leu 210 215 220 Thr Val Ser Asn GlyThr Leu Gly Leu Ala Ile Lys Arg Pro Leu Ile 225 230 235 240 Ile Gln AspAsn Asn Leu Phe Leu Asp Phe Arg Ala Pro Leu Arg Leu 245 250 255 Phe AsnSer Asp Pro Val Leu Gly Leu Asn Phe Tyr Thr Pro Leu Ala 260 265 270 ValArg Asp Glu Ala Leu Thr Val Asn Thr Gly Arg Gly Leu Thr Val 275 280 285Ser Tyr Asp Gly Leu Ile Leu Asn Leu Gly Lys Asp Leu Arg Phe Asp 290 295300 Asn Asn Thr Val Ser Val Ala Leu Ser Ala Ala Leu Pro Leu Gln Tyr 305310 315 320 Thr Asp Gln Leu Arg Leu Asn Val Gly Ala Gly Leu Arg Tyr AsnPro 325 330 335 Val Ser Lys Lys Leu Asp Val Asn Pro Asn Gln Asn Lys GlyLeu Thr 340 345 350 Trp Glu Asn Asp Tyr Leu Ile Val Lys Leu Gly Asn GlyLeu Gly Phe 355 360 365 Asp Gly Asp Gly Asn Ile Ala Val Ser Pro Gln ValThr Ser Pro Asp 370 375 380 Thr Leu Trp Thr Thr Ala Asp Pro Ser Pro AsnCys Ser Ile Tyr Thr 385 390 395 400 Asp Leu Asp Ala Lys Met Trp Leu SerLeu Val Lys Gln Gly Gly Val 405 410 415 Val His Gly Ser Val Ala Leu LysAla Leu Lys Gly Thr Leu Leu Ser 420 425 430 Pro Thr Glu Ser Ala Ile ValIle Ile Leu His Phe Asp Asn Tyr Gly 435 440 445 Val Arg Ile Leu Asn TyrPro Thr Leu Gly Thr Gln Gly Thr Leu Gly 450 455 460 Asn Asn Ala Thr TrpGly Tyr Arg Gln Gly Glu Ser Ala Asp Thr Asn 465 470 475 480 Val Leu AsnAla Leu Ala Phe Met Pro Ser Ser Lys Arg Tyr Pro Arg 485 490 495 Gly ArgGly Ser Glu Val Gln Asn Gln Thr Val Gly Tyr Thr Cys Ile 500 505 510 GlnGly Asp Phe Ser Met Pro Val Pro Tyr Gln Ile Gln Tyr Asn Tyr 515 520 525Gly Pro Thr Gly Tyr Ser Phe Lys Phe Ile Trp Arg Thr Val Ser Arg 530 535540 Gln Pro Phe Asp Ile Pro Cys Cys Phe Phe Ser Tyr Ile Thr Glu Glu 545550 555 560 29 31044 DNA simian adenovirus SV-25 CDS (12284)..(13801)Penton 29 catcatcaat aatatacctt attctggaaa cgtgccaata tgataatgagcggggaggag 60 cgaggcgggg ccggggtgac gtgcggtgac gcggggtggc gcgagggcggggcgaagggc 120 gcgggtgtgt gtgtgggagg cgcttagttt ttacgtatgc ggaaggaggttttataccgg 180 aagatgggta atttgggcgt atacttgtaa gttttgtgta atttggcgcgaaaactgggt 240 aatgaggaag ttgaggttaa tatgtacttt ttatgactgg gcggaatttctgctgatcag 300 cagtgaactt tgggcgctga cggggaggtt tcgctacgtg acagtaccacgagaaggctc 360 aaaggtccca tttattgtac tcttcagcgt tttcgctggg tatttaaacgctgtcagatc 420 atcaagaggc cactcttgag tgctggcgag aagagttttc tcctccgtgctgccacgatg 480 aggctggtcc ccgagatgta cggtgttttt agcgacgaga cggtgcgtaactcagatgac 540 ctgctgaatt cagacgcgct ggaaatttcc aattcgcctg tgctttcgccgccgtcactt 600 cacgacctgt ttgtgttttg gctcaacgct tagcaacgtg ttatatagggtcaagaagga 660 gcaggagacg cagtttgcta ggctgttggc cgatactcct ggagtttttgtggctctgga 720 tctaggccat cactctcttt tccaagagaa aattatcaaa aacttaacttttacgtctcc 780 tggtcgcacg gttgcttccg ctgcctttat tacctatatt ttggatcaatggagcaacag 840 cgacagccac ctgtcgtggg agtacatgct ggattacatg tcgatggcgctgtggagggc 900 catgctgcgg aggagggttt gcatttactt gcgggcgcag cctccgcggctggaccgagt 960 ggaggaggag gacgagccgg gggagaccga gaacctgagg gccgggctggaccctccaac 1020 ggaggactag gtgctgagga tgatcccgaa gaggggacta gtggggctaggaagaagcaa 1080 aagactgagt ctgaacctcg aaactttttg aatgagttga ctgtgagtttgatgaatcgt 1140 cagcgtccgg agacaatttt ctggtctgaa ttggaggagg aattcaggaggggggaactg 1200 aacctgctat acaagtatgg gtttgaacag ttaaaaactc actggttggagccgtgggag 1260 gattttgaaa ccgccttgga cacttttgct aaagtggctc tgcggccggataaggtttac 1320 actatccgcc gcactgttaa cataaagaag agtgtttatg ttataggccatggagctctg 1380 gtgcaggtgc aaaccgtcga ccgggtggcc tttagttgcg gtatgcaaaatctgggcccc 1440 ggggtgatag gcttaaatgg tgtaacattt cacaatgtaa ggtttactggtgaaagtttt 1500 aacggctctg tgtttgcaaa taacacacag ctgacgctcc acggcgtttacttttttaac 1560 tttaataaca catgtgtgga gtcgtggggc agggtgtctt tgaggggctgctgttttcac 1620 ggctgctgga aggcggtggt gggaagactt aaaagtgtaa catctgtaaaaaaatgcgtg 1680 tttgagcggt gtgtgttggc tttaactgtg gagggctgtg gacgcattaggaataatgcg 1740 gcgtctgaga atggatgttt tcttttgcta aaaggcacgg ctagtattaagcataacatg 1800 atatgcggca gcggtctgta cccttcacag ctgttaactt gcgcggatggaaactgtcag 1860 accttgcgca ccgtgcacat agcgtcccac cagcgccgcg cctggccaacattcgagcac 1920 aatatgctta tgcgttgtgc cgtccacttg ggccctaggc gaggcgtgtttgtgccttac 1980 cagtgtaact ttagccatac caagatttta ctagaacctg ataccttctctcgagtgtgt 2040 ttcaatgggg tgtttgacat gtcaatggaa ctgtttaaag tgataagatatgatgaatcc 2100 aagtctcgtt gtcgcccatg tgaatgcgga gctaatcatc tgaggttgtatcctgtaacc 2160 ctaaacgtta ccgaggagct gaggacggat caccacatgt tgtcctgcctgcgcaccgac 2220 tatgaatcca gcgacgagga gtgaggtgag gggcggagcc acaaagggtataaaggggcg 2280 tgaggggtgg gtgtgatgat tcaaaatgag cgggacgacg gacggcaacgcgtttgaggg 2340 tggagtgttc agcccttatc tgacatctcg tcttccttcc tgggcaggagtgcgtcagaa 2400 tgtagtgggc tccaccgtgg acggacgacc ggtcgcccct gcaaattccgccaccctcac 2460 ctatgccacc gtgggatcat cgttggacac tgccgcggca gctgccgcttctgctgccgc 2520 ttctactgct cgcggcatgg cggctgattt tggactgtat aaccaactggccactgcagc 2580 tgtggcgtct cggtctctgg ttcaagaaga tgccctgaat gtgatcctgactcgcctgga 2640 gatcatgtca cgtcgcttgg acgaactggc tgcgcagata tcccaagctaaccccgatac 2700 cacttcagaa tcctaaaata aagacaaaca aatatgttga aaagtaaaatggctttattt 2760 gttttttttg gctcggtagg ctcgggtcca cctgtctcgg tcgttaagaactttgtgtat 2820 gttttccaaa acacggtaca gatgggcttg gatgttcaag tacatgggcatgaggccatc 2880 tttggggtga agataggacc attgaagagc gtcatgctcc ggggtggtgttgtaaattac 2940 ccagtcgtag cagggtttct gggcgtggaa ctggaagatg tcctttaggagtaggctgat 3000 ggccaagggc aggcccttag tgtaggtgtt tacaaagcgg ttaagctgggagggatgcat 3060 gcggggggag atgatatgca tcttggcttg gatcttgagg ttagctatgttaccacccag 3120 gtctctgcgg gggttcatgt tatgaaggac caccagcacg gtgtagccggtgcatttggg 3180 gaacttgtca tgcagtttgg aggggaaggc gtggaagaat ttagagacccccttgtggcc 3240 ccctaggttt tccatgcact catccataat gatggcaatg ggacccctggcggccgcttt 3300 ggcaaacacg ttttgggggt tggaaacatc atagttttgc tctagagtgagctcatcata 3360 ggccatctta acaaagcggg gtaggagggt gcccgactgg gggatgatagttccatctgg 3420 gcctggggcg tagttaccct cacagatctg catctcccag gccttaatttccgagggggg 3480 tatcatgtcc acctgggggg caataaagaa cacggtttct ggcgggggattgatgagctg 3540 ggtggaaagc aagttacgca gcagttgaga tttgccacag ccggtggggccgtagatgac 3600 cccgatgacg ggttgcagct ggtagttgag agaggaacag ctgccgtcggggcgcaggag 3660 gggggctacc tcattcatca tgcttctaac atgtttattt tcactcactaagttttgcaa 3720 gagcctctcc ccacccaggg ataagagttc ttccaggctg ttgaagtgtttcagcggttt 3780 taggccgtcg gccatgggca tcttttcgag cgactgacga agcaagtacagtcggtccca 3840 gagctcggtg acgtgctcta tggaatctcg atccagcaga cttcttggttgcgggggttg 3900 ggtcgacttt cgctgtaggg caccagccgg tgggcgtcca gggccgcgagggttctgtcc 3960 ttccagggtc tcagcgtccg ggtgagggtg gtctcggtga cggtgaagggatgagccccg 4020 ggctgggcgc ttgcgagggt gcgcttcagg ctcatcctgc tggtgctgaagcggacgtcg 4080 tctccctgtg agtcggccag atagcaacga agcatgaggt cgtagctgagggactcggcc 4140 gcgtgtccct tggcgcgcag ctttcccttg gaaacgtgct gacatttggtgcagtgcaga 4200 cattggaggg cgtagagttt gggggccagg aagaccgact cgggcgagtaggcgtcggct 4260 ccgcactgag cgcagacggt ctcgcactcc actagccacg tgagctcgggtttagcggga 4320 tcaaaaacca agttgcctcc attttttttg atgcgtttct taccttgcgtttccatgagt 4380 ttgtggcccg cttccgtgac aaaaaggctg tcggtgtctc cgtagacagacttgaggggg 4440 cgatcttcca aaggtgttcc gaggtcttcc gcgtacagga actgggaccactccgagacg 4500 aaggctctgg tccaggctaa cacgaaggag gcaatctgcg aggggtatctgtcgttttca 4560 atgagggggt ccaccttttc cagggtgtgc agacacaggt cgtcctcctccgcgtccacg 4620 aaggtgattg gcttgtaagt gtaggtcacg tgatctgcac cccccaaaggggtataaaag 4680 ggggcgtgcc caccctctcc gtcactttct tccgcatcgc tgtggaccagagccagctgt 4740 tcgggtgagt aggccctctc aaaagccggc atgatctcgg cgctcaagttgtcagtttct 4800 acaaacgagg tggatttgat attcacgtgc cccgcggcga tgcttttgatggtggagggg 4860 tccatctgat cagaaaacac gatctttttg ttgtcaagtt tggtggcgaaagacccgtag 4920 agggcgttgg aaagcaactt ggcgatggag cgcagggtct gatttttctcccgatcggcc 4980 ctctccttgg cggcgatgtt gagttgcacg tactcccggg ccgcgcaccgccactcgggg 5040 aacacggcgg tgcgctcgtc gggcaggatg cgcacgcgcc agccgcgattgtgcagggtg 5100 atgaggtcca cgctggtagc cacctccccg cggaggggct cgttggtccaacacaatcgc 5160 cccccttttc tggagcagaa cggaggcagg ggatctagca agttggcgggcggggggtcg 5220 gcgtcgatgg tgaagatacc gggtagcagg atcttattaa aataatcgatttcggtgtcc 5280 gtgtcttgca acgcgtcttc ccacttcttc accgccaggg ccctttcgtagggattcagg 5340 ggcggtcccc agggcatggg gtgggtcagg gccgaggcgt acatgccgcagatgtcatac 5400 acgtacaggg gttccctcaa caccccgatg taagtggggt aacagcgccccccgcggatg 5460 ctggctcgca cgtagtcgta catctcgcgc gagggagcca tgaggccgtctcccaagtgg 5520 gtcttgtggg gtttttcggc ccggtagagg atctgtctga agatggcgtgggagttggaa 5580 gagatggtgg ggcgttggaa gacgttaaag ttggccccgg gtagtcccacggagtcttgg 5640 atgaactggg cgtaggattc ccggagtttg tccaccaggg cggcggtcaccagcacgtcg 5700 agagcgcagt agtccaacgt ctcgcggacc aggttgtagg ccgtctcttgttttttctcc 5760 cacagttcgc ggttgaggag gtattcctcg cggtctttcc agtactcttcggcgggaaat 5820 cctttttcgt ccgctcggta agaacctaac atgtaaaatt cgttcaccgctttgtatgga 5880 caacagcctt tttctaccgg cagggcgtac gcttgagcgg cctttctgagagaggtgtgg 5940 gtgagggcga aggtgtcccg caccatcact ttcaggtact gatgtttgaagtccgtgtcg 6000 tcgcaggcgc cctgttccca cagcgtgaag tcggtgcgct ttttctgcctgggattgggg 6060 agggcgaagg tgacatcgtt aaagagtatt ttcccggcgc ggggcatgaagttgcgagag 6120 atcctgaagg gcccgggcac gtccgagcgg ttgttgatga cctgcgccgccaggacgatc 6180 tcgtcgaagc cgttgatgtt gtgacccacg atgtaaagtt cgatgaagcgcggctgtccc 6240 ttgagggccg gcgctttttt caactcctcg taggtgagac agtccggcgaggagagaccc 6300 agctcagccc gggcccagtc ggagagttga ggattagccg caaggaaggagctccataga 6360 tccaaggcca ggagagtttg caagcggtcg cggaactcgc ggaactttttccccacggcc 6420 attttctccg gtgtcactac gtaaaaggtg ttggggcggt tgttccacacgtcccatcgg 6480 agctctaggg ccagctcgca ggcttggcga acgagggtct cctcgccagagacgtgcatg 6540 accagcataa agggtaccaa ctgtttcccg aacgagccca tccatgtgtaggtttctacg 6600 tcgtaggtga caaagagccg ctgggtgcgc gcgtgggagc cgatcggaaagaagctgatc 6660 tcctgccacc agctggagga atgggtgtta atgtggtgga agtagaagtcccgccggcgc 6720 acagagcatt cgtgctgatg tttgtaaaag cgaccgcagt agtcgcagcgctgcacgctc 6780 tgtatctcct gaacgagatg cgcttttcgc ccgcgcacca gaaaccggagggggaagttg 6840 agacgggggg ctggtggggc gacatcccct tcgccttggc ggtgggagtctgcgtctgcg 6900 tcctccttct ctgggtggac gacggtgggg acgacgacgc cccgggtgccgcaagtccag 6960 atctccgcca cggaggggtg caggcgctgc aggaggggac gcagctgcccgctgtccagg 7020 gagtcgaggg aagtcgcgct gaggtcggcg ggaagcgttt gcaagttcactttcagaaga 7080 ccggtaagag cgtgagccag gtgcagatgg tacttgattt ccaggggggtgttggatgaa 7140 gcgtccacgg cgtagaggag tccgtgtccg cgcggggcca ccaccgtgccccgaggaggt 7200 tttatctcac tcgtcgaggg cgagcgccgg ggggtagagg cggctctgcgccggggggca 7260 gcggaggcag aggcacgttt tcgtgaggat tcggcagcgg ttgatgacgagcccggagac 7320 tgctggcgtg ggcgacgacg cggcggttga ggtcctggat gtgccgtctctgcgtgaaga 7380 ccaccggccc ccgggtcctg aacctaaaga gagttccaca gaatcaatgtctgcatcgtt 7440 aacggcggcc tgcctgagga tctcctgcac gtcgcccgag ttgtcctgataggcgatctc 7500 ggccatgaac tgttccactt cttcctcgcg gaggtcaccg tggcccgctcgctccacggt 7560 ggcggccagg tcgttggaga tgcggcgcat gagttgagag aaggcgttgaggccgttctc 7620 gttccacacg cggctgtaca ccacgtttcc gaaggagtcg cgcgctcgcatgaccacctg 7680 ggccacgttg agttccacgt ggcgggcgaa gacggcgtag tttctgaggcgctggaagag 7740 gtagttgagc gtggtggcga tgtgctcgca gacgaagaag tacataatccagcgccgcag 7800 ggtcatctcg ttgatgtctc cgatggcttc gagacgctcc atggcctcgtagaagtcgac 7860 ggcgaagttg aaaaattggg agttgcgggc ggccaccgtg agttcttcttgcaggaggcg 7920 gatgagatcg gcgaccgtgt cgcgcacctc ctgttcgaaa gcgccccgaggcgcctctgc 7980 ttcttcctcc ggctcctcct cttccagggg ctcgggttcc tccggcagctctgcgacggg 8040 gacggggcgg cgacgtcgtc gtctgaccgg caggcggtcc acgaagcgctcgatcatttc 8100 gccgcgccgg cgacgcatgg tctcggtgac ggcgcgtccg ttttcgcgaggtcgcagttc 8160 gaagacgccg ccgcgcagag cgcccccgtg cagggagggt aagtggttagggccgtcggg 8220 cagggacacg gcgctgacga tgcattttat caattgctgc gtaggcactccgtgcaggga 8280 tctgagaacg tcgaggtcga cgggatccga gaacttctct aggaaagcgtctatccaatc 8340 gcaatcgcaa ggtaagctga gaacggtggg tcgctggggg gcgttcgcgggcagttggga 8400 ggtgatgctg ctgatgatgt aattaaagta ggcggtcttc aggcggcggatggtggcgag 8460 gaggaccacg tctttgggcc cggcctgttg aatgcgcagg cgctcggccatgccccaggc 8520 ctcgctctga cagcgacgca ggtctttgta gaagtcttgc atcagtctctccaccggaac 8580 ctctgcttct cccctgtctg ccatgcgagt cgagccgaac ccccgcaggggctgcagcaa 8640 cgctaggtcg gccacgaccc tttcggccag cacggcctgt tgaatctgcgtgagggtggc 8700 ctggaagtcg tccaggtcca cgaagcggtg ataggccccc gtgttgatggtgtaggtgca 8760 gttggccatg acggaccagt tgacgacttg catgccgggt tgggtgatctccgtgtactt 8820 gaggcgcgag taggccctgg actcgaacac gtagtcgttg catgtgcgcaccagatactg 8880 gtagccgacc aggaagtgag gaggcggctc tcggtacagg ggccagccaacggtggcggg 8940 ggcgccgggg gacaggtcgt ccagcatgag gcggtggtag tggtagatgtagcgggagag 9000 ccaggtgatg ccggccgagg tggttgcggc cctggtgaat tcgcggacgcggttccagat 9060 gttgcgcagg ggaccaaagc gctccatggt gggcacgctc tgccccgtgaggcgggcgca 9120 atcttgtacg ctctagatgg aaaaaagaca gggcggtcat cgactcctttccgtagcttg 9180 gggggtaaag tcgcaagggt gcggcggcgg ggaaccccgg ttcgagaccggccggatccg 9240 ccgctcccga tgcgcctggc cccgcatcca cgacgtccgc gccgagacccagccgcgacg 9300 ctccgcccca atacggaggg gagtcttttg gtgttttttc gtagatgcatccggtgctgc 9360 ggcagatgcg accccagacg cccactacca ccgccgtggc ggcagtaaacctgagcggag 9420 gcggtgacag ggaggaggaa gagctggctt tagacctgga agagggagaggggctggccc 9480 ggctgggagc gccatcccca gagagacacc ctagggttca gctcgtgagggacgccaggc 9540 aggcttttgt gccgaagcag aacctgttta gggaccgcag cggtcaggaggcggaggaga 9600 tgcgcgattg caggtttcgg gcgggcagag agctcagggc gggcttcgatcgggagcggc 9660 tcctgagggc ggaggatttc gagcccgacg agcgttctgg ggtgagcccggcccgcgctc 9720 acgtatcggc ggccaacctg gtgagcgcgt acgagcagac ggtgaacgaggagcgcaact 9780 tccaaaagag ctttaacaat cacgtgagga ccctgatcgc gagggaggaggtgaccatcg 9840 ggctgatgca tctgtgggac ttcgtggagg cctacgtgca gaacccggctagcaaacccc 9900 tgacggccca gctgttcctg atcgtgcagc acagccgcga caacgagacgttccgcgacg 9960 ccatgttgaa catcgcggag cccgagggtc gctggctctt ggatctgattaacatcctgc 10020 agagcatcgt ggtgcaggag aggggcctga gtttagcgga caaggtggcggccattaact 10080 attcgatgca gagcctgggg aagttctacg ctcgcaagat ctacaagagcccttacgtgc 10140 ccatagacaa ggaggtgaag atagacagct tttacatgcg catggcgctgaaggtgctga 10200 cgctgagcga cgacctcggc gtgtaccgta acgacaagat ccacaaggcggtgagcgcca 10260 gccgccggcg ggagctgagc gacagggagc tgatgcacag cctgcagagggcgctggcgg 10320 gcgccgggga cgaggagcgc gaggcttact tcgacatggg agccgatctgcagtggcgtc 10380 ccagcgcgcg cgccttggag gcggcgggtt atcccgacga ggaggatcgggacgatttgg 10440 aggaggcagg cgagtacgag gacgaagcct gaccgggcag gtgttgttttagatgcagcg 10500 gccggcggac gggaccaccg cggatcccgc acttttggca tccatgcagagtcaaccttc 10560 gggcgtgacc gcctccgatg actgggcggc ggccatggac cgcatcatggcgctgaccac 10620 ccgcaacccc gaggctttta ggcagcaacc ccaggccaac cgtttttcggccatcttgga 10680 agcggtggtg ccgtcgcgca ccaacccgac gcacgagaaa gtcctgactatcgtgaacgc 10740 cctggtagac agcaaggcca tccgccgtga cgaggcgggc ttgatttacaacgctctttt 10800 ggaacgcgtg gcgcgctaca acagcactaa cgtgcagacc aatctggaccgcctcaccac 10860 cgacgtgaag gaggcgctgg cgcagaagga gcggtttctg agggacagtaatctgggctc 10920 tctggtggca ctgaacgcct tcctgagctc acagccggcc aacgtgccccgcgggcagga 10980 ggattacgtg agcttcatca gcgctctgag actgctggtg tccgaggtgccccagagcga 11040 ggtgtaccag tctgggccgg attacttttt ccagacgtcc cgacagggcttgcaaacggt 11100 gaacctgact caggccttta aaaacttgca aggcatgtgg ggggtcaaggccccggtggg 11160 cgatcgcgcc actatctcca gtctgctgac ccccaacact cgcctgctgctgctcttgat 11220 cgcaccgttt accaacagta gcactatcag ccgtgactcg tacctgggtcatctcatcac 11280 tctgtaccgc gaggccatcg gccaggctca gatcgacgag catacgtatcaggagattac 11340 taacgtgagc cgtgccctgg gtcaggaaga taccggcagc ctggaagccacgttgaactt 11400 tttgctaacc aaccggaggc aaaaaatacc ctcccagttc acgttaagcgccgaggagga 11460 gaggattctg cgatacgtgc agcagtccgt gagcctgtac ttgatgcgcgagggcgccac 11520 cgcttccacg gctttagaca tgacggctcg gaacatggaa ccgtccttttactccgccca 11580 ccggccgttc attaaccgtc tgatggacta cttccatcgc gcggccgccatgaacgggga 11640 gtacttcacc aatgccatcc tgaatccgca ttggatgccc ccgtccggcttctacaccgg 11700 ggagtttgac ctgcccgaag ccgacgacgg ctttctgtgg gacgacgtgtccgatagcat 11760 tttcacgccg gctaatcgcc gattccagaa gaaggagggc ggagacgagctccccctctc 11820 cagcgtggaa gcggcctcaa ggggagagag tccctttcca agtctgtcttccgccagtag 11880 cggtcgggta acgcgtccac ggttgccggg ggagagcgac tacctgaacgaccccttgct 11940 gcgaccggct agaaagaaaa attttcccaa taacggggtg gaaagcttggtggataaaat 12000 gaatcgttgg aagacgtacg cccaggagca gcgggagtgg gaggacagtcagccgcggcc 12060 gctggtaccg ccgcattggc gtcgccagag agaagacccg gacgactccgcagacgatag 12120 tagcgtgttg gacctgggag ggagcggagc caaccccttt gctcacttgcaacccaaggg 12180 gcgctcgagt cgcctgtatt aataaaaaag acgcggaaac ttaccagagccatggccaca 12240 gcgtgtgtgc tttcttcctc tctttcttcc tcggcgcggc aga atg agaaga gcg 12295 Met Arg Arg Ala 1 gtg aga gtc acg ccg gcg gcg tat gag ggcccg ccc cct tct tac gaa 12343 Val Arg Val Thr Pro Ala Ala Tyr Glu GlyPro Pro Pro Ser Tyr Glu 5 10 15 20 agc gtg atg gga tca gcg aac gtg ccggcc acg ctg gag gcg cct tac 12391 Ser Val Met Gly Ser Ala Asn Val ProAla Thr Leu Glu Ala Pro Tyr 25 30 35 gtt cct ccc aga tac ctg gga cct acggag ggc aga aac agc atc cgt 12439 Val Pro Pro Arg Tyr Leu Gly Pro ThrGlu Gly Arg Asn Ser Ile Arg 40 45 50 tac tcc gag ctg gcg ccc ctg tac gatacc acc aag gtg tac ctg gtg 12487 Tyr Ser Glu Leu Ala Pro Leu Tyr AspThr Thr Lys Val Tyr Leu Val 55 60 65 gac aac aag tcg gcg gac atc gcc tccctg aat tac caa aac gat cac 12535 Asp Asn Lys Ser Ala Asp Ile Ala SerLeu Asn Tyr Gln Asn Asp His 70 75 80 agt aac ttt ctg act acc gtg gtg cagaac aat gac ttc acc ccg acg 12583 Ser Asn Phe Leu Thr Thr Val Val GlnAsn Asn Asp Phe Thr Pro Thr 85 90 95 100 gag gcg ggc acg cag acc att aacttt gac gag cgt tcc cgc tgg ggc 12631 Glu Ala Gly Thr Gln Thr Ile AsnPhe Asp Glu Arg Ser Arg Trp Gly 105 110 115 ggt cag ctg aaa acc atc ctgcac acc aac atg ccc aac atc aac gag 12679 Gly Gln Leu Lys Thr Ile LeuHis Thr Asn Met Pro Asn Ile Asn Glu 120 125 130 ttc atg tcc acc aac aagttc agg gct aag ctg atg gta gaa aaa agt 12727 Phe Met Ser Thr Asn LysPhe Arg Ala Lys Leu Met Val Glu Lys Ser 135 140 145 aat gcg gaa act cggcag ccc cga tac gag tgg ttc gag ttt acc att 12775 Asn Ala Glu Thr ArgGln Pro Arg Tyr Glu Trp Phe Glu Phe Thr Ile 150 155 160 cca gag ggc aactat tcc gaa act atg act atc gat ctc atg aat aac 12823 Pro Glu Gly AsnTyr Ser Glu Thr Met Thr Ile Asp Leu Met Asn Asn 165 170 175 180 gcg atcgtg gac aat tac ctg caa gtg ggg aga cag aac ggg gtg ctg 12871 Ala IleVal Asp Asn Tyr Leu Gln Val Gly Arg Gln Asn Gly Val Leu 185 190 195 gaaagc gat atc ggc gtg aaa ttc gat acc aga aac ttc cga ctg ggg 12919 GluSer Asp Ile Gly Val Lys Phe Asp Thr Arg Asn Phe Arg Leu Gly 200 205 210tgg gat ccc gtg acc aag ctg gtg atg cca ggc gtg tac acc aac gag 12967Trp Asp Pro Val Thr Lys Leu Val Met Pro Gly Val Tyr Thr Asn Glu 215 220225 gct ttt cac ccg gac atc gtg ctg ctg ccg ggg tgc ggt gtg gac ttc13015 Ala Phe His Pro Asp Ile Val Leu Leu Pro Gly Cys Gly Val Asp Phe230 235 240 act cag agc cgt ttg agt aac ctg tta gga att aga aag cgc cgcccc 13063 Thr Gln Ser Arg Leu Ser Asn Leu Leu Gly Ile Arg Lys Arg ArgPro 245 250 255 260 ttc caa gag ggc ttt caa atc atg tat gag gac ctg gaggga ggt aat 13111 Phe Gln Glu Gly Phe Gln Ile Met Tyr Glu Asp Leu GluGly Gly Asn 265 270 275 ata ccc gcc tta ctg gac gtg tcg aag tac gaa gctagc ata caa cgc 13159 Ile Pro Ala Leu Leu Asp Val Ser Lys Tyr Glu AlaSer Ile Gln Arg 280 285 290 gcc aaa gcg gag ggt aga gag att cgg gga gacacc ttt gcg gta gct 13207 Ala Lys Ala Glu Gly Arg Glu Ile Arg Gly AspThr Phe Ala Val Ala 295 300 305 ccc cag gac ctg gaa ata gtg cct tta actaaa gac agc aaa gac aga 13255 Pro Gln Asp Leu Glu Ile Val Pro Leu ThrLys Asp Ser Lys Asp Arg 310 315 320 agc tac aat att ata aac aac acg acggac acc ctg tat cgg agc tgg 13303 Ser Tyr Asn Ile Ile Asn Asn Thr ThrAsp Thr Leu Tyr Arg Ser Trp 325 330 335 340 ttt ctg gct tac aac tac ggagac ccc gag aaa gga gtg aga tca tgg 13351 Phe Leu Ala Tyr Asn Tyr GlyAsp Pro Glu Lys Gly Val Arg Ser Trp 345 350 355 acc ata ctc acc acc acggac gtg acc tgt ggc tcg cag caa gtg tac 13399 Thr Ile Leu Thr Thr ThrAsp Val Thr Cys Gly Ser Gln Gln Val Tyr 360 365 370 tgg tcc ctg ccg gatatg atg caa gac ccg gtc acc ttc cgc ccc tcc 13447 Trp Ser Leu Pro AspMet Met Gln Asp Pro Val Thr Phe Arg Pro Ser 375 380 385 acc caa gtc agcaac ttc ccg gtg gtg ggc acc gag ctg ctg ccc gtc 13495 Thr Gln Val SerAsn Phe Pro Val Val Gly Thr Glu Leu Leu Pro Val 390 395 400 cat gcc aagagc ttc tac aac gag cag gcc gtc tac tcg caa ctt att 13543 His Ala LysSer Phe Tyr Asn Glu Gln Ala Val Tyr Ser Gln Leu Ile 405 410 415 420 cgccag tcc acc gcg ctt acc cac gtg ttc aat cgc ttt ccc gag aac 13591 ArgGln Ser Thr Ala Leu Thr His Val Phe Asn Arg Phe Pro Glu Asn 425 430 435cag att ctg gtg cgc cct ccc gct cct acc att acc acc gtc agt gaa 13639Gln Ile Leu Val Arg Pro Pro Ala Pro Thr Ile Thr Thr Val Ser Glu 440 445450 aac gtt ccc gcc ctc aca gat cac gga acc ctg ccg ctg cgc agc agt13687 Asn Val Pro Ala Leu Thr Asp His Gly Thr Leu Pro Leu Arg Ser Ser455 460 465 atc agt gga gtt cag cgc gtg acc atc acc gac gcc aga cgt cgaacc 13735 Ile Ser Gly Val Gln Arg Val Thr Ile Thr Asp Ala Arg Arg ArgThr 470 475 480 tgc ccc tac gtt tac aaa gcg ctt ggc gtg gtg gct cct aaagtt ctt 13783 Cys Pro Tyr Val Tyr Lys Ala Leu Gly Val Val Ala Pro LysVal Leu 485 490 495 500 tct agt cgc acc ttc taa aaacatgtcc atcctcatctctcccgataa 13831 Ser Ser Arg Thr Phe 505 caacaccggc tggggactgggctccggcaa gatgtacggc ggagccaaaa ggcgctccag 13891 tcagcaccca gttcgagttcggggccactt ccgcgctcct tggggagctt acaagcgagg 13951 actctcgggt cgaacggctgtagacgatac catagatgcc gtgattgccg acgcccgccg 14011 gtacaacccc ggaccggtcgctagcgccgc ctccaccgtg gattccgtga tcgacagcgt 14071 ggtagccggc gctcgggcctatgctcgccg caagaggcgg ctgcatcgga gacgtcgccc 14131 caccgccgcc atgctggcagccagggccgt gctgaggcgg gcccggaggg caggcagaag 14191 ggctatgcgc cgcgctgccgccaacgccgc cgccgggagg gcccgccgac aggctgcccg 14251 ccaggctgcc gctgccatcgctagcatggc cagacccagg agagggaacg tgtactgggt 14311 gcgtgattct gtgacgggagtccgagtgcc ggtgcgcagc cgacctcccc gaagttagaa 14371 gatccaagct gcgaagacggcggtactgag tctccctgtt gttatcagcc caacatgagc 14431 aagcgcaagt ttaaagaagaactgctgcag acgctggtgc ctgagatcta tggccctccg 14491 gacgtgaagc cagacattaagccccgcgat atcaagcgtg ttaaaaagcg ggaaaagaaa 14551 gaggaactcg cggtggtagacgatggcgga gtggaattta ttaggagttt cgccccgcga 14611 cgcagggttc aatggaaagggcggcgggta caacgcgttt tgaggccggg caccgcggta 14671 gtttttaccc cgggagagcggtcggccgtt aggggtttca aaaggcagta cgacgaggtg 14731 tacggcgacg aggacatattggaacaggcg gctcaacaga tcggagaatt tgcctacgga 14791 aagcgttcgc gtcgcgaagacctggccatc gccttagaca gcggcaaccc cacgcccagc 14851 ctcaaacccg tgacgctgcagcaggtgctt cccgtgagcg ccagcacgga cagcaagagg 14911 gggattaaga gagaaatggaagatctgcat cccaccatcc aactcatggt ccctaaacgg 14971 cagaggctgg aagaggtcctggagaagatg aaagtggacc ccagcataga gccggatgta 15031 aaagtcagac ctattaaggaagtggccccc ggtcttgggg tgcaaacggt ggacattcaa 15091 atccccgtca ccaccgcttcaaccgccgtg gaagctatgg aaacgcaaac ggagacccct 15151 gccgcgatcg gtaccagggaagtggcgttg caaacggagc cttggtacga atacgcagcc 15211 cctcggcgtc agaggcgttccgctcgttac ggccccgcca acgccatcat gccagaatat 15271 gcgctgcatc cgtctattctgcccactccc ggataccggg gtgtgacgta tcgcccgtct 15331 ggaacccgcc gccgaacccgtcgccgccgc cgctcccgtc gcgctctggc ccccgtgtcg 15391 gtgcggcgtg tgacccgccggggaaagaca gtcgtcattc ccaacccgcg ttaccaccct 15451 agcatccttt aataactctgccgttttgca gatggctctg acttgccgcg tgcgccttcc 15511 cgttccgcac tatcgaggaagatctcgtcg taggagaggc atgacgggca gtggtcgccg 15571 gcgggctttg cgcaggcgcatgaaaggcgg aattttaccc gccctgatac ccataattgc 15631 cgccgccatc ggtgccatacccggcgttgc ttcagtggcg ttgcaagcag ctcgtaataa 15691 ataaacaaag gcttttgcacttatgacctg gtcctgacta ttttatgcag aaagagcatg 15751 gaagacatca attttacgtcgctggctccg cggcacggct cgcggccgct catgggcacc 15811 tggaacgaca tcggcaccagtcagctcaac gggggcgctt tcaattgggg gagcctttgg 15871 agcggcatta aaaactttggctccacgatt aaatcctacg gcagcaaagc ctggaacagt 15931 agtgctggtc agatgctccgagataaactg aaggacacca acttccaaga aaaagtggtc 15991 aatggggtgg tgaccggcatccacggcgcg gtagatctcg ccaaccaagc ggtgcagaaa 16051 gagattgaca ggcgtttggaaagctcgcgg gtgccgccgc agagagggga tgaggtggag 16111 gtcgaggaag tagaagtagaggaaaagctg cccccgctgg agaaagttcc cggtgcgcct 16171 ccgagaccgc agaagcggcccaggccagaa ctagaagaga ctctggtgac ggagagcaag 16231 gagcctccct cgtacgagcaagccttgaaa gagggcgcct ctccaccctc ctacccgatg 16291 actaagccga tcgcacccatggctcgaccg gtgtacggca aggattacaa gcccgtcacg 16351 ctagagctgc ccccaccgccccccacgcgc ccgaccgtcc cccccctgcc gactccgtcg 16411 gcggccgcgg cgggacccgtgtccgcacca tccgctgtgc ctctgccagc cgcccgtcca 16471 gtggccgtgg ccactgccagaaaccccaga ggccagagag gagccaactg gcaaagcacg 16531 ctgaacagca tcgtgggcctgggagtgaaa agcctgaaac gccgccgttg ctattattaa 16591 aaaagtgtag ctaaaaagtctcccgttgta tacgcctcct atgttaccgc cagagacgag 16651 tgactgtcgc cgcgagcgccgctttcaag atg gcc acc cca tcg atg atg ccg 16704 Met Ala Thr Pro Ser MetMet Pro 510 cag tgg tct tac atg cac atc gcc ggc cag gac gcc tcg gag tacctg 16752 Gln Trp Ser Tyr Met His Ile Ala Gly Gln Asp Ala Ser Glu TyrLeu 515 520 525 agt ccc ggc ctc gtg cag ttt gcc cgc gcc acc gac acc tacttc agc 16800 Ser Pro Gly Leu Val Gln Phe Ala Arg Ala Thr Asp Thr TyrPhe Ser 530 535 540 545 ttg gga aac aag ttt aga aac ccc acc gtg gcc cccacc cac gat gtg 16848 Leu Gly Asn Lys Phe Arg Asn Pro Thr Val Ala ProThr His Asp Val 550 555 560 acc acg gac cgc tcg cag agg ctg acc ctg cgcttt gtg ccc gta gac 16896 Thr Thr Asp Arg Ser Gln Arg Leu Thr Leu ArgPhe Val Pro Val Asp 565 570 575 cgg gag gac acc gcg tac tct tac aaa gtgcgc tac acg ttg gcc gta 16944 Arg Glu Asp Thr Ala Tyr Ser Tyr Lys ValArg Tyr Thr Leu Ala Val 580 585 590 ggg gac aac cga gtg ctg gac atg gccagc acc tac ttt gac atc cgg 16992 Gly Asp Asn Arg Val Leu Asp Met AlaSer Thr Tyr Phe Asp Ile Arg 595 600 605 ggg gtg ctg gat cgg ggt ccc agcttc aag ccc tat tcc ggc acc gct 17040 Gly Val Leu Asp Arg Gly Pro SerPhe Lys Pro Tyr Ser Gly Thr Ala 610 615 620 625 tac aac tcc ctg gcc cccaag gga gct ccc aac ccc tcg gaa tgg acg 17088 Tyr Asn Ser Leu Ala ProLys Gly Ala Pro Asn Pro Ser Glu Trp Thr 630 635 640 gac act tcc gac aacaaa ctt aaa gca tat gct cag gct ccc tac cag 17136 Asp Thr Ser Asp AsnLys Leu Lys Ala Tyr Ala Gln Ala Pro Tyr Gln 645 650 655 agt caa gga cttaca aag gat ggt att cag gtt ggg cta gtt gtg aca 17184 Ser Gln Gly LeuThr Lys Asp Gly Ile Gln Val Gly Leu Val Val Thr 660 665 670 gag tca ggacaa aca ccc caa tat gca aac aaa gtg tac caa ccc gag 17232 Glu Ser GlyGln Thr Pro Gln Tyr Ala Asn Lys Val Tyr Gln Pro Glu 675 680 685 cca caaatt ggg gaa aac caa tgg aat tta gaa caa gaa gat aaa gcg 17280 Pro GlnIle Gly Glu Asn Gln Trp Asn Leu Glu Gln Glu Asp Lys Ala 690 695 700 705gcg gga aga gtc cta aag aaa gat acc cct atg ttt ccc tgc tat ggg 17328Ala Gly Arg Val Leu Lys Lys Asp Thr Pro Met Phe Pro Cys Tyr Gly 710 715720 tca tat gcc agg ccc aca aac gaa caa gga ggg cag gca aaa aac caa17376 Ser Tyr Ala Arg Pro Thr Asn Glu Gln Gly Gly Gln Ala Lys Asn Gln725 730 735 gaa gta gat tta cag ttt ttt gcc act ccg ggc gac acc cag aacacg 17424 Glu Val Asp Leu Gln Phe Phe Ala Thr Pro Gly Asp Thr Gln AsnThr 740 745 750 gct aaa gtg gta ctt tat gct gaa aat gtc aac ctg gaa actcca gat 17472 Ala Lys Val Val Leu Tyr Ala Glu Asn Val Asn Leu Glu ThrPro Asp 755 760 765 act cac tta gtg ttt aaa ccc gat gac gac agc acc agttca aaa ctt 17520 Thr His Leu Val Phe Lys Pro Asp Asp Asp Ser Thr SerSer Lys Leu 770 775 780 785 ctt ctt ggg cag cag gct gca cct aac aga cccaac tac ata ggt ttt 17568 Leu Leu Gly Gln Gln Ala Ala Pro Asn Arg ProAsn Tyr Ile Gly Phe 790 795 800 aga gat aat ttt att ggt tta atg tac tacaat agc act gga aac atg 17616 Arg Asp Asn Phe Ile Gly Leu Met Tyr TyrAsn Ser Thr Gly Asn Met 805 810 815 ggc gtg ctg gcc gga cag gct tct caattg aat gcc gta gtc gac ttg 17664 Gly Val Leu Ala Gly Gln Ala Ser GlnLeu Asn Ala Val Val Asp Leu 820 825 830 cag gac aga aac acc gag ttg tcctac cag ctg atg ctg gac gca ctg 17712 Gln Asp Arg Asn Thr Glu Leu SerTyr Gln Leu Met Leu Asp Ala Leu 835 840 845 ggg gat cgc agc cga tat ttttca atg tgg aat cag gca gta gac agc 17760 Gly Asp Arg Ser Arg Tyr PheSer Met Trp Asn Gln Ala Val Asp Ser 850 855 860 865 tat gac cca gac gttaga att ata gaa aac cac gga gtg gaa gac gaa 17808 Tyr Asp Pro Asp ValArg Ile Ile Glu Asn His Gly Val Glu Asp Glu 870 875 880 ctg cca aac tattgt ttt cct ctg gga gga atg gtg gtg act gac aat 17856 Leu Pro Asn TyrCys Phe Pro Leu Gly Gly Met Val Val Thr Asp Asn 885 890 895 tac aac tctgtg acg cct caa aat gga ggc agt gga aat aca tgg cag 17904 Tyr Asn SerVal Thr Pro Gln Asn Gly Gly Ser Gly Asn Thr Trp Gln 900 905 910 gca gacaat act aca ttt agt caa aga gga gcg cag att ggc tcc gga 17952 Ala AspAsn Thr Thr Phe Ser Gln Arg Gly Ala Gln Ile Gly Ser Gly 915 920 925 aacatg ttt gcc ctg gaa att aac cta cag gcc aac ctc tgg cgc ggc 18000 AsnMet Phe Ala Leu Glu Ile Asn Leu Gln Ala Asn Leu Trp Arg Gly 930 935 940945 ttc ttg tat tcc aat att ggg ttg tat ctt cca gac tct ctg aaa atc18048 Phe Leu Tyr Ser Asn Ile Gly Leu Tyr Leu Pro Asp Ser Leu Lys Ile950 955 960 acc ccc gac aac atc acg ctg cca gaa aac aaa aac act tat cagtac 18096 Thr Pro Asp Asn Ile Thr Leu Pro Glu Asn Lys Asn Thr Tyr GlnTyr 965 970 975 atg aac ggt cgc gta acg cca ccc ggg ctc ata gac acc tatgta aac 18144 Met Asn Gly Arg Val Thr Pro Pro Gly Leu Ile Asp Thr TyrVal Asn 980 985 990 gtg ggc gcg cgc tgg tcc ccc gat gtc atg gac agc attaac ccc ttc 18192 Val Gly Ala Arg Trp Ser Pro Asp Val Met Asp Ser IleAsn Pro Phe 995 1000 1005 aac cac cac cgt aac gcg ggc ttg cgc tac cgctcc atg ctc ttg 18237 Asn His His Arg Asn Ala Gly Leu Arg Tyr Arg SerMet Leu Leu 1010 1015 1020 ggc aac ggc cgt tat gtg cct ttt cac att caggtg ccc caa aaa 18282 Gly Asn Gly Arg Tyr Val Pro Phe His Ile Gln ValPro Gln Lys 1025 1030 1035 ttc ttt gcc att aaa aac ctg ctg ctt ctc cccggt tcc tat acc 18327 Phe Phe Ala Ile Lys Asn Leu Leu Leu Leu Pro GlySer Tyr Thr 1040 1045 1050 tat gag tgg aac ttc cgc aag gat gtc aac atgatc ctg cag agc 18372 Tyr Glu Trp Asn Phe Arg Lys Asp Val Asn Met IleLeu Gln Ser 1055 1060 1065 tcg ctg ggt aat gac ctg cga gtg gac ggg gccagc ata cgc ttt 18417 Ser Leu Gly Asn Asp Leu Arg Val Asp Gly Ala SerIle Arg Phe 1070 1075 1080 gac agc att aac ctg tat gcc aac ttt ttt cccatg gcc cac aac 18462 Asp Ser Ile Asn Leu Tyr Ala Asn Phe Phe Pro MetAla His Asn 1085 1090 1095 acg gcc tct acc ctg gaa gcc atg ctg cgc aacgac acc aat gac 18507 Thr Ala Ser Thr Leu Glu Ala Met Leu Arg Asn AspThr Asn Asp 1100 1105 1110 cag tcc ttc aac gac tac ctg tgc gcg gct aacatg ctg tac ccc 18552 Gln Ser Phe Asn Asp Tyr Leu Cys Ala Ala Asn MetLeu Tyr Pro 1115 1120 1125 atc ccc gcc aac gcc acc agc gtg ccc att tctatt cct tct cgg 18597 Ile Pro Ala Asn Ala Thr Ser Val Pro Ile Ser IlePro Ser Arg 1130 1135 1140 aac tgg gct gcc ttc agg ggc tgg agt ttt actcgc ctc aaa acc 18642 Asn Trp Ala Ala Phe Arg Gly Trp Ser Phe Thr ArgLeu Lys Thr 1145 1150 1155 aag gag act ccc tcg ctg ggc tcc ggt ttt gacccc tac ttt gtt 18687 Lys Glu Thr Pro Ser Leu Gly Ser Gly Phe Asp ProTyr Phe Val 1160 1165 1170 tac tcc ggc tcc att ccc tac cta gat ggc accttt tac ctc aac 18732 Tyr Ser Gly Ser Ile Pro Tyr Leu Asp Gly Thr PheTyr Leu Asn 1175 1180 1185 cac act ttc aaa aag gtg tct att atg ttt gactcc tcg gtt agc 18777 His Thr Phe Lys Lys Val Ser Ile Met Phe Asp SerSer Val Ser 1190 1195 1200 tgg ccc ggc aac gac cgc ctg cta acg ccc aacgag ttc gaa att 18822 Trp Pro Gly Asn Asp Arg Leu Leu Thr Pro Asn GluPhe Glu Ile 1205 1210 1215 aag cgt tcc gtg gac ggt gaa ggg tac aac gtggcc cag agc aac 18867 Lys Arg Ser Val Asp Gly Glu Gly Tyr Asn Val AlaGln Ser Asn 1220 1225 1230 atg acc aag gac tgg ttt cta att caa atg ctcagt cac tat aat 18912 Met Thr Lys Asp Trp Phe Leu Ile Gln Met Leu SerHis Tyr Asn 1235 1240 1245 ata ggt tac cag ggc ttc tat gtg ccc gag aactac aag gac cgc 18957 Ile Gly Tyr Gln Gly Phe Tyr Val Pro Glu Asn TyrLys Asp Arg 1250 1255 1260 atg tac tcc ttc ttc cgc aac ttc caa cca atgagc cgg cag gtg 19002 Met Tyr Ser Phe Phe Arg Asn Phe Gln Pro Met SerArg Gln Val 1265 1270 1275 gta gat acc gtg act tat aca gac tac aaa gatgtc aag ctc ccc 19047 Val Asp Thr Val Thr Tyr Thr Asp Tyr Lys Asp ValLys Leu Pro 1280 1285 1290 tac caa cac aac aac tca ggg ttc gtg ggc tacatg gga ccc acc 19092 Tyr Gln His Asn Asn Ser Gly Phe Val Gly Tyr MetGly Pro Thr 1295 1300 1305 atg cga gag gga cag gcc tac ccg gcc aac tatccc tac ccc ctg 19137 Met Arg Glu Gly Gln Ala Tyr Pro Ala Asn Tyr ProTyr Pro Leu 1310 1315 1320 atc gga gag act gcc gta ccc agc ctc acg cagaaa aag ttc ctc 19182 Ile Gly Glu Thr Ala Val Pro Ser Leu Thr Gln LysLys Phe Leu 1325 1330 1335 tgc gac cgg gtg atg tgg agg ata ccc ttc tctagc aac ttt atg 19227 Cys Asp Arg Val Met Trp Arg Ile Pro Phe Ser SerAsn Phe Met 1340 1345 1350 tcg atg ggc tcc ctc acc gac ctg ggg cag aacatg ctg tac gcc 19272 Ser Met Gly Ser Leu Thr Asp Leu Gly Gln Asn MetLeu Tyr Ala 1355 1360 1365 aac tcc gct cac gcc ttg gac atg act ttt gaggtg gat ccc atg 19317 Asn Ser Ala His Ala Leu Asp Met Thr Phe Glu ValAsp Pro Met 1370 1375 1380 gat gag ccc acg ctt ctc tat gtt ctg ttt gaagtc ttc gac gtg 19362 Asp Glu Pro Thr Leu Leu Tyr Val Leu Phe Glu ValPhe Asp Val 1385 1390 1395 gtg cgc atc cac cag ccg cac cgc ggc gtc atcgag gcc gtc tac 19407 Val Arg Ile His Gln Pro His Arg Gly Val Ile GluAla Val Tyr 1400 1405 1410 ctg cgc aca cct ttc tct gcc ggt aac gcc accacc taa agaagctgat 19456 Leu Arg Thr Pro Phe Ser Ala Gly Asn Ala Thr Thr1415 1420 1425 gggttccagc gaacaggagt tgcaggccat tgttcgcgac ctgggctgcgggccctgctt 19516 tttgggcacc ttcgacaagc gttttcccgg attcatgtcc ccccacaagccggcctgcgc 19576 catcgttaac acggccggac gggagacagg gggggtgcac tggctcgccttcgcctggaa 19636 cccgcgcaac cgcacctgct acctgttcga cccttttggt ttctccgacgaaaggctgaa 19696 gcagatctac caattcgagt acgaggggct cctcaagcgc agcgctctggcctccacgcc 19756 cgaccactgc gtcaccctgg aaaagtccac ccagacggtc caggggcccctctcggccgc 19816 ctgcgggctt ttctgttgca tgtttttgca cgccttcgtg cactggcctcacacccccat 19876 ggagcgcaac cccaccatgg atctgctcac cggagtgccc aacagcatgcttcacagtcc 19936 ccaggtcgcc cccaccctgc gtcgcaatca ggaccacctg tatcgctttctggggaaaca 19996 ctctgcctat ttccgccgcc accggcagcg catcgaacag gccacggccttcgaaagcat 20056 gagccaaaga gtgtaatcaa taaaaaccgt ttttatttga catgatacgcgcttctggcg 20116 tttttattaa aaatcgaagg gttcgaggga ggggtcctcg tgcccgctggggagggacac 20176 gttgcggtac tggaatcggg cgctccaacg aaactcgggg atcaccagccgcggcagggc 20236 cacgtcttcc atgttctgct tccaaaactg tcgcaccagc tgcagggctcccatcacgtc 20296 gggcgctgag atcttgaagt cgcagttagg gccggagccc ccgcggctgttgcggaacac 20356 ggggttggca cactggaaca ccaacacgct ggggttgtgg atactagccagggccgtcgg 20416 gtcggtcacc tccgatgcat ccagatcctc ggcattgctc agggcgaacggggtcagctt 20476 gcacatctgc cgcccgatct ggggtaccag gtcgcgcttg ttgaggcagtcgcagcgcag 20536 agggatgagg atgcgacgct gcccgcgttg catgatgggg taactcgccgccaggaactc 20596 ctctatctga cggaaggcca tctgggcctt gacgccctcg gtgaaaaatagcccacagga 20656 cttgctggaa aacacgttat tgccacagtt gatgtcttcc gcgcagcagcgcgcatcttc 20716 gttcttcagc tgaaccacgt tgcgacccca gcggttctga accaccttggctttcgtggg 20776 atgctccttc agcgcccgct gtccgttctc gctggtcaca tccatttccaccacgtgctc 20836 cttgcagacc atctccactc cgtggaaaca gaacagaatg ccctcctgttgggtattgcg 20896 atgctcccac acggcgcacc cggtggactc ccagctcttg tgtttcacccccgcgtaggc 20956 ttccatgtaa gccattagaa atctgcccat cagctcagtg aaggtcttctggttggtgaa 21016 ggttagcggc aggccgcggt gttcctcgtt caaccaagtt tgacagatcttgcggtacac 21076 ggctccctgg tcgggcagaa acttaaaagt cgttctgctc tcgttgtccacgtggaactt 21136 ctccatcaac atcgtcatga cttccatgcc cttctcccag gcagtcaccagcggcgcgct 21196 ctcggggttc ttcaccaaca cggcggtgga ggggccctcg ccggccccgacgtccttcat 21256 ggacattttt tgaaactcca cggtgccgtc cgcgcggcgt actctgcgcatcggagggta 21316 gctgaagccc acctccatga cggtgctttc gccctcgctg tcggagacgatctccgggga 21376 gggcggcgga acgggggcag acttgcgagc cttcttcttg ggagggagcggaggcacctc 21436 ctgctcgcgc tcgggactca tctcccgcaa gtagggggtg atggagcttcctggttggtt 21496 ctgacggttg gccattgtat cctaggcaga aagacatgga gcttatgcgcgaggaaactt 21556 taaccgcccc gtcccccgtc agcgacgaag aggtcatcgt cgaacaggacccgggctacg 21616 ttacgccgcc cgaggatctg gaggggccct tagacgaccg gcgcgacgctagtgagcggc 21676 aggaaaatga gaaagaggag gaggagggct gctacctcct ggaaggcgacgttttgctaa 21736 agcatttcgc caggcagagc accatactca aggaggcctt gcaagaccgctccgaggtgc 21796 ccttggacgt cgccgcgctc tcccaggcct acgaggcgaa ccttttctcgccccgagtgc 21856 ctccgaagag acagcccaac ggcacctgcg agcccaaccc gcgactcaacttctaccccg 21916 tgttcgccgt gcccgaggcg ctggccacct accacatctt tttcaaaaaccagcgcattc 21976 ccctttcctg ccgggccaac cgcaccgcgg ccgataggaa gctaacactcagaaacggag 22036 tcagcatacc tgatatcacg tcactggagg aagtgcctaa gatcttcgagggtctgggtc 22096 gagatgagaa gcgggcggcg aacgctctgc agaaagaaca gaaagagagtcagaacgtgc 22156 tggtggagct ggagggggac aacgcgcgtc tgaccgtcct caaacgttgcatagaagttt 22216 cccacttcgc ctacccggcc ctcaacctgc cgcccaaagt tatgaaatcggtcatggacc 22276 agctactcat caagagagct gagcccctga atcccgacca ccctgaggcggaaaactcag 22336 aggacggaaa gcccgtcgtc agcgacgagg agctcgagcg gtggctggaaaccagggacc 22396 cccagcagtt gcaagagagg cgcaagatga tgatggcggc cgtgctggtcacggtggagc 22456 tagaatgcct gcaacggttt ttcagcgacg tggagacgct acgcaaaatcggggagtccc 22516 tgcactacac cttccgccag ggctacgttc gccaggcctg caaaatctccaacgtagagc 22576 tcagcaacct ggtttcctac atgggcatcc tccacgagaa ccggctggggcagagcgtgc 22636 tgcactgcac cttgcaaggc gaggcgcgaa gggactacgt ccgagactgcgtctacctct 22696 tcctcaccct cacctggcag accgccatgg gcgtgtggca gcagtgcttggaagagagaa 22756 acctcaaaga gctggacaaa ctcctctgcc gccagcggcg ggccctctggaccggcttca 22816 gcgagcgcac ggtcgcctgc gccctggcag acatcatttt cccagaacgcctgatgaaaa 22876 ccttgcagaa cggcctgccg gatttcatca gtcagagcat cttgcaaaacttccgctcct 22936 tcgtcctgga gcgctccggg atcttgcccg ccatgagctg cgcgctgccttctgactttg 22996 tccccctttc ctaccgcgag tgccctcccc cactgtggag ccactgctacctcttccaac 23056 tggccaactt tctggcctac cactccgacc tcatggaaga cgtgagcggagaggggctgc 23116 tcgagtgcca ctgccgctgc aacctctgca ccccccacag atcgctggcctgcaacaccg 23176 agctgctcag cgaaacccag gtcataggta ccttcgagat ccaggggccccagcagcaag 23236 agggtgcttc cggcttgaag ctcactccgg cgctgtggac ctcggcttacttacgcaaat 23296 ttgtagccga ggactaccac gcccacaaaa ttcagtttta cgaagaccaatctcgaccac 23356 cgaaagcccc cctcacggcc tgcgtcatca cccagagcaa aatcctggcccaattgcaat 23416 ccatcaacca agcgcgccga gatttccttt tgaaaaaggg tcggggggtgtacctggacc 23476 cccagaccgg cgaggaactc aacccgtcca cactttccgt cgaagcagcccccccgagac 23536 atgccaccca agggaaccgc caagcagctg atcgctcggc agagagcgaagaagcaagag 23596 ctgctccagc agcaggtgga ggacgaggaa gagctgtggg acagccaggcagaggaggtg 23656 tcagaggacg aggaggagat ggaaagctgg gacagcctag acgaggaggacgagctttca 23716 gaggaagagg cgaccgaaga aaaaccacct gcatccagcg cgccttctctgagccgacag 23776 ccgaagcccc ggcccccgac gcccccggcc ggctcactca aagccagccgtaggtgggac 23836 gccaccggat ctccagcggc agcggcaacg gcagcgggta aggccaaacgcgagcggcgg 23896 gggtattgct cctggcggac ccacaaaagc agtatcgtga actgcttgcaacactgcggg 23956 ggaaacatct cctttgcccg acgctacctc ctcttccatc acggtgtggccttccctcgc 24016 aacgttctct attattaccg tcatctctac agcccctacg aaacgctcggagaaaaaagc 24076 taaggcctcc tctgccgcga ggaaaaactc cgccgccgct gccgccaaggatccgccggc 24136 caccgaggag ctgagaaagc gcatctttcc cactctgtat gctatctttcagcaaagccg 24196 cgggcagcac cctcagcgcg aactgaaaat aaaaaaccgc tccttccgctcactcacccg 24256 cagctgtctg taccacaaga gagaagacca gctgcagcgc accctggacgacgccgaagc 24316 actgttcagc aaatactgct cagcgtctct taaagactaa aagacccgcgctttttcccc 24376 ctcgggcgcc aaaacccacg tcatcgccag catgagcaag gagattcccaccccttacat 24436 gtggagctat cagccccaga tgggcctggc cgcgggggcc gcccaggactactccagcaa 24496 aatgaactgg ctcagcgccg gcccccacat gatctcacga gttaacggcatccgagccca 24556 ccgaaaccag atcctcttag aacaggcggc aatcaccgcc acaccccggcgccaactcaa 24616 cccgcccagt tggcccgccg cccaggtgta tcaggaaact ccccgcccgaccacagtcct 24676 cctgccacgc gacgcggagg ccgaagtcct catgactaac tctggggtacaattagcggg 24736 cgggtccagg tacgccaggt acagaggtcg ggccgctcct tactctcccgggagtataaa 24796 gagggtgatc attcgaggcc gaggtatcca gctcaacgac gaggcggtgagctcctcaac 24856 cggtctcaga cctgacggag tcttccagct cggaggagcg ggccgctcttccttcaccac 24916 tcgccaggcc tacctgaccc tgcagagctc ttcctcgcag ccgcgctccgggggaatcgg 24976 cactctccag ttcgtggaag agttcgtccc ctccgtctac ttcaacccgttttccggctc 25036 acctggacgc tacccggacg ccttcattcc caactttgac gcagtgagtgaatccgtgga 25096 cggctacgac tgatgacaga tggtgcggcc gtgagagctc ggctgcgacatctgcatcac 25156 tgccgccagc ctcgctgcta cgctcgggag gcgatcgtgt tcagctactttgagctgccg 25216 gacgagcacc ctcagggacc ggctcacggg ttgaaactcg agattgagaacgcgcttgag 25276 tctcacctca tcgacgcctt caccgcccgg cctctcctgg tagaaaccgaacgcgggatc 25336 actaccatca ccctgttctg catctgcccc acgcccggat tac atg aagatc tgt 25391 Met Lys Ile Cys 1430 gtt gtc atc ttt gcg ctc agt tta ataaaa act gaa ctt ttt gcc 25436 Val Val Ile Phe Ala Leu Ser Leu Ile LysThr Glu Leu Phe Ala 1435 1440 1445 gta cct tca acg cca cgc gtt gtt tctcct tgt gaa aaa acc cca 25481 Val Pro Ser Thr Pro Arg Val Val Ser ProCys Glu Lys Thr Pro 1450 1455 1460 gga gtc ctt aac tta cac ata gca aaaccc ttg tat ttt acc ata 25526 Gly Val Leu Asn Leu His Ile Ala Lys ProLeu Tyr Phe Thr Ile 1465 1470 1475 gaa aaa caa cta gcc ctt tca att ggaaaa ggg tta aca att tct 25571 Glu Lys Gln Leu Ala Leu Ser Ile Gly LysGly Leu Thr Ile Ser 1480 1485 1490 gct aca gga cag ttg gaa agc aca gcaagc gta cag gac agc gct 25616 Ala Thr Gly Gln Leu Glu Ser Thr Ala SerVal Gln Asp Ser Ala 1495 1500 1505 aca cca ccc cta cgt ggt att tcc ccttta aag ctg aca gac aac 25661 Thr Pro Pro Leu Arg Gly Ile Ser Pro LeuLys Leu Thr Asp Asn 1510 1515 1520 ggt tta aca tta agc tat tca gat cccctg cgt gtg gta ggt gac 25706 Gly Leu Thr Leu Ser Tyr Ser Asp Pro LeuArg Val Val Gly Asp 1525 1530 1535 caa ctt acg ttt aat ttt act tct ccacta cgt tac gaa aat ggc 25751 Gln Leu Thr Phe Asn Phe Thr Ser Pro LeuArg Tyr Glu Asn Gly 1540 1545 1550 agt ctt aca ttc aac tac act tct cccatg aca cta ata aac aac 25796 Ser Leu Thr Phe Asn Tyr Thr Ser Pro MetThr Leu Ile Asn Asn 1555 1560 1565 agt ctt gct att aac gtc aat acc tccaaa ggc ctc agt agt gac 25841 Ser Leu Ala Ile Asn Val Asn Thr Ser LysGly Leu Ser Ser Asp 1570 1575 1580 aac ggc aca ctc gct gta aat gtt actcca gat ttt aga ttt aac 25886 Asn Gly Thr Leu Ala Val Asn Val Thr ProAsp Phe Arg Phe Asn 1585 1590 1595 agc tct ggt gcc tta act ttt ggc atacaa agt cta tgg act ttt 25931 Ser Ser Gly Ala Leu Thr Phe Gly Ile GlnSer Leu Trp Thr Phe 1600 1605 1610 cca acc aaa act cct aac tgt acc gtgttt acc gaa agt gac tcc 25976 Pro Thr Lys Thr Pro Asn Cys Thr Val PheThr Glu Ser Asp Ser 1615 1620 1625 ctg ctg agt ctt tgc ttg act aaa tgcgga gct cac gta ctt gga 26021 Leu Leu Ser Leu Cys Leu Thr Lys Cys GlyAla His Val Leu Gly 1630 1635 1640 agc gtg agt tta agc gga gtg gca ggaacc atg cta aaa atg acc 26066 Ser Val Ser Leu Ser Gly Val Ala Gly ThrMet Leu Lys Met Thr 1645 1650 1655 cac act tct gtt acc gtt cag ttt tcgttt gat gac agt ggt aaa 26111 His Thr Ser Val Thr Val Gln Phe Ser PheAsp Asp Ser Gly Lys 1660 1665 1670 cta ata ttc tct cca ctt gcg aac aacact tgg ggt gtt cga caa 26156 Leu Ile Phe Ser Pro Leu Ala Asn Asn ThrTrp Gly Val Arg Gln 1675 1680 1685 agc gag agt ccg ttg ccc aac cca tccttc aac gct ctc acg ttt 26201 Ser Glu Ser Pro Leu Pro Asn Pro Ser PheAsn Ala Leu Thr Phe 1690 1695 1700 atg cca aac agt acc att tat tct agagga gca agt aac gaa cct 26246 Met Pro Asn Ser Thr Ile Tyr Ser Arg GlyAla Ser Asn Glu Pro 1705 1710 1715 caa aac aat tat tat gtc cag acg tatctt aga ggc aac gtg cga 26291 Gln Asn Asn Tyr Tyr Val Gln Thr Tyr LeuArg Gly Asn Val Arg 1720 1725 1730 aag cca att cta cta act gtt acc tacaac tca gtt aat tca gga 26336 Lys Pro Ile Leu Leu Thr Val Thr Tyr AsnSer Val Asn Ser Gly 1735 1740 1745 tat tcc tta act ttt aaa tgg gat gctgtc gcc aat gaa aaa ttt 26381 Tyr Ser Leu Thr Phe Lys Trp Asp Ala ValAla Asn Glu Lys Phe 1750 1755 1760 gcc act cct aca tct tcg ttt tgc tatgtt gca gag caa taa 26423 Ala Thr Pro Thr Ser Ser Phe Cys Tyr Val AlaGlu Gln 1765 1770 aaccctgtta ccccaccgtc tcgttttttt cag atg aaa cga gcgaga gtt 26474 Met Lys Arg Ala Arg Val 1775 gat gaa gac ttc aac cca gtgtac cct tat gac ccc cca tac gct 26519 Asp Glu Asp Phe Asn Pro Val TyrPro Tyr Asp Pro Pro Tyr Ala 1780 1785 1790 ccc gtc atg ccc ttc att actccg cct ttt acc tcc tcg gat ggg 26564 Pro Val Met Pro Phe Ile Thr ProPro Phe Thr Ser Ser Asp Gly 1795 1800 1805 ttg cag gaa aaa cca ctt ggagtg tta agt tta aac tac agg gat 26609 Leu Gln Glu Lys Pro Leu Gly ValLeu Ser Leu Asn Tyr Arg Asp 1810 1815 1820 ccc att act aca caa aat gggtct ctc acg tta aaa cta gga aac 26654 Pro Ile Thr Thr Gln Asn Gly SerLeu Thr Leu Lys Leu Gly Asn 1825 1830 1835 ggc ctc act cta aac aac caggga cag tta aca tca act gct ggc 26699 Gly Leu Thr Leu Asn Asn Gln GlyGln Leu Thr Ser Thr Ala Gly 1840 1845 1850 gaa gtg gag cct ccg ctc actaat gct aac aac aaa ctt gca cta 26744 Glu Val Glu Pro Pro Leu Thr AsnAla Asn Asn Lys Leu Ala Leu 1855 1860 1865 gcc tat agc gaa cca tta gcagta aaa agc aac cgc cta act cta 26789 Ala Tyr Ser Glu Pro Leu Ala ValLys Ser Asn Arg Leu Thr Leu 1870 1875 1880 tca cac acc gct ccc ctt gtcatc gct aat aat tct tta gcg ttg 26834 Ser His Thr Ala Pro Leu Val IleAla Asn Asn Ser Leu Ala Leu 1885 1890 1895 caa gtt tca gag cct att tttgta aat gac gat gac aag cta gcc 26879 Gln Val Ser Glu Pro Ile Phe ValAsn Asp Asp Asp Lys Leu Ala 1900 1905 1910 ctg cag aca gcc gcc ccc cttgta acc aac gct ggc acc ctt cgc 26924 Leu Gln Thr Ala Ala Pro Leu ValThr Asn Ala Gly Thr Leu Arg 1915 1920 1925 tta cag agc gct gcc cct ttagga ttg gtt gaa aat act ctt aaa 26969 Leu Gln Ser Ala Ala Pro Leu GlyLeu Val Glu Asn Thr Leu Lys 1930 1935 1940 ctg ctg ttt tct aaa ccc ttgtat ttg caa aat gat ttt ctt gca 27014 Leu Leu Phe Ser Lys Pro Leu TyrLeu Gln Asn Asp Phe Leu Ala 1945 1950 1955 tta gcc att gaa cgc ccc ctggct gta gca gcc gca ggt act ctg 27059 Leu Ala Ile Glu Arg Pro Leu AlaVal Ala Ala Ala Gly Thr Leu 1960 1965 1970 acc cta caa ctt act cct ccatta aag act aac gat gac ggg cta 27104 Thr Leu Gln Leu Thr Pro Pro LeuLys Thr Asn Asp Asp Gly Leu 1975 1980 1985 aca cta tcc aca gtc gag ccatta act gta aaa aac gga aac cta 27149 Thr Leu Ser Thr Val Glu Pro LeuThr Val Lys Asn Gly Asn Leu 1990 1995 2000 ggc ttg caa ata tcg cgc ccttta gtt gtt caa aac aac ggc ctt 27194 Gly Leu Gln Ile Ser Arg Pro LeuVal Val Gln Asn Asn Gly Leu 2005 2010 2015 tcg ctt gct att acc ccc ccgctg cgt ttg ttt aac agc gac ccc 27239 Ser Leu Ala Ile Thr Pro Pro LeuArg Leu Phe Asn Ser Asp Pro 2020 2025 2030 gtt ctt ggt ttg ggc ttc actttt ccc cta gct gtc aca aac aac 27284 Val Leu Gly Leu Gly Phe Thr PhePro Leu Ala Val Thr Asn Asn 2035 2040 2045 ctc ctc tcc tta aac atg ggagac gga gtt aaa ctt acc tat aat 27329 Leu Leu Ser Leu Asn Met Gly AspGly Val Lys Leu Thr Tyr Asn 2050 2055 2060 aaa cta aca gcc aat ttg ggtagg gat tta caa ttt gaa aac ggt 27374 Lys Leu Thr Ala Asn Leu Gly ArgAsp Leu Gln Phe Glu Asn Gly 2065 2070 2075 gcg att gcc gta acg ctt actgcc gaa tta cct ttg caa tac act 27419 Ala Ile Ala Val Thr Leu Thr AlaGlu Leu Pro Leu Gln Tyr Thr 2080 2085 2090 aac aaa ctt caa ctg aat attgga gct ggc ctt cgt tac aat gga 27464 Asn Lys Leu Gln Leu Asn Ile GlyAla Gly Leu Arg Tyr Asn Gly 2095 2100 2105 gcc agc aga aaa cta gat gtaaac att aac caa aat aaa ggc tta 27509 Ala Ser Arg Lys Leu Asp Val AsnIle Asn Gln Asn Lys Gly Leu 2110 2115 2120 act tgg gac aac gat gca gttatt ccc aaa cta gga tcg ggc tta 27554 Thr Trp Asp Asn Asp Ala Val IlePro Lys Leu Gly Ser Gly Leu 2125 2130 2135 caa ttt gac cct aat ggc aacatc gct gtt atc cct gaa acc gtg 27599 Gln Phe Asp Pro Asn Gly Asn IleAla Val Ile Pro Glu Thr Val 2140 2145 2150 aag ccg caa acg tta tgg acgact gca gat ccc tcg cct aac tgc 27644 Lys Pro Gln Thr Leu Trp Thr ThrAla Asp Pro Ser Pro Asn Cys 2155 2160 2165 tca gtg tac cag gac ttg gatgcc agg ctg tgg ctc gct ctt gtt 27689 Ser Val Tyr Gln Asp Leu Asp AlaArg Leu Trp Leu Ala Leu Val 2170 2175 2180 aaa agt ggc gac atg gtg catgga agc att gcc cta aaa gcc cta 27734 Lys Ser Gly Asp Met Val His GlySer Ile Ala Leu Lys Ala Leu 2185 2190 2195 aaa ggg acg ttg cta aat cctaca gcc agc tac att tcc att gtg 27779 Lys Gly Thr Leu Leu Asn Pro ThrAla Ser Tyr Ile Ser Ile Val 2200 2205 2210 ata tat ttt tac agc aac ggagtc agg cgt acc aac tat cca acg 27824 Ile Tyr Phe Tyr Ser Asn Gly ValArg Arg Thr Asn Tyr Pro Thr 2215 2220 2225 ttt gac aac gaa ggc acc ttagct aac agc gcc act tgg gga tac 27869 Phe Asp Asn Glu Gly Thr Leu AlaAsn Ser Ala Thr Trp Gly Tyr 2230 2235 2240 cga cag ggg caa tct gct aacact aat gtg acc aat gcc act gaa 27914 Arg Gln Gly Gln Ser Ala Asn ThrAsn Val Thr Asn Ala Thr Glu 2245 2250 2255 ttt atg ccc agc tca agc aggtac ccc gtg aat aaa gga gac aac 27959 Phe Met Pro Ser Ser Ser Arg TyrPro Val Asn Lys Gly Asp Asn 2260 2265 2270 att caa aat caa tct ttt tcatac acc tgt att aaa gga gat ttt 28004 Ile Gln Asn Gln Ser Phe Ser TyrThr Cys Ile Lys Gly Asp Phe 2275 2280 2285 gct atg cct gtc ccg ttc cgtgta aca tat aat cac gcc ctg gaa 28049 Ala Met Pro Val Pro Phe Arg ValThr Tyr Asn His Ala Leu Glu 2290 2295 2300 ggg tat tcc ctt aag ttc acctgg cgc gtt gta gcc aat cag gcc 28094 Gly Tyr Ser Leu Lys Phe Thr TrpArg Val Val Ala Asn Gln Ala 2305 2310 2315 ttt gat att cct tgc tgt tcattt tca tac atc aca gaa taa 28136 Phe Asp Ile Pro Cys Cys Ser Phe SerTyr Ile Thr Glu 2320 2325 2330 aaaaccactt tttcatttta atttctttttattttacacg aacagtgaga cttcctccac 28196 ccttccattt gacagcatac accagcctctcccccttcat agcagtaaac tgttgtgaat 28256 cagtccggta tttgggagtt aaaatccaaacagtctcttt ggtgatgaaa cgtcgatcag 28316 taatggacac aaatccctgg gacaggttttccaacgtttc ggtgaaaaac tgcacaccgc 28376 cctacaaaac aaacaggttc aggctctccacgggttatct ccccgatcaa actcagacag 28436 ggtaaaggtg cggtggtgtt ccactaaaccacgcaggtgg cgctgtctga acctctcggt 28496 gcgactcctg tgaggctggt aagaagttagattgtccagt agcctcacag catgtatcat 28556 cagtctacga gtgcgtctgg cgcagcagcgcatctgaatc tcactgagat tccggcaaga 28616 atcgcacacc atcacaatca ggttgttcatgatcccatag ctgaacacgc tccagccaaa 28676 gctcattcgc tccaacagcg ccaccgcgtgtccgtccaac cttactttaa cataaatcag 28736 gtgtctgccg cgtacaaaca tgctacccacatacagaact tcccggggca ggcccctgtt 28796 caccacctgt ctgtaccagg gaaacctcacatttatcagg gagccataga tggccatttt 28856 aaaccaatta gctaataccg ccccaccagctctacactga agagaaccgg gagagttaca 28916 atgacagtga ataatccatc tctcataacccctgatggtc tgatgaaaat ctagatctaa 28976 cgtggcacaa caaatacaca ctttcatatacattttcata acatgttttt cccaggccgt 29036 taaaatacaa tcccaataca cgggccactcctgcagtaca ataaagctaa tacaagatgg 29096 tatactcctc acctcactga cactgtgcatgttcatattt tcacattcta agtaccgaga 29156 gttctcctct acagcagcac tgctgcggtcctcacaaggt ggtagctggt gatgattgta 29216 gggggccagt ctgcagcgat accgtctgtcgcgttgcatc gtagaccagg aaccgacgca 29276 cctcctcgta cttgtggtag cagaaccacgtccgctgcca gcacgtctcc acgtaacgcc 29336 ggtccctgcg tcgctcacgc tccctcctcaatgcaaagtg caaccactct tgtaatccac 29396 acagatccct ctcggcctcc ggggtgatgcacacctcaaa cctacagatg tctcggtaca 29456 gttccaaaca cgtagtgagg gcgagttccaaccaagacag acagcctgat ctatcccgac 29516 acactggagg tggaggaaga cacggaagaggcatgttatt ccaagcgatt caccaacggg 29576 tcgaaatgaa gatcccgaag atgacaacggtcgcctccgg agccctgatg gaatttaaca 29636 gccagatcaa acgttatgcg attctccaagctatcgatcg ccgcttccaa aagagcctgg 29696 acccgcactt ccacaaacac cagcaaagcaaaagcactat tatcaaactc ttcaatcatc 29756 aagctgcagg actgtacaat gcctaagtaattttcgtttc tccactcgcg aatgatgtcg 29816 cggcagatag tctgaaggtt catcccgtgcagggtaaaaa gctccgaaag ggcgccctct 29876 acagccatgc gtagacacac catcatgactgcaagatatc gggctcctga gacacctgca 29936 gcagatttaa cagatcaagg tcaggttgctctccgcgatc acgaatctcc atccgcaagg 29996 tcatttgcaa aaaattaaat aaatctatgccgactagatc tgtcaactcc gcattaggaa 30056 ccaaatcagg tgtggctacg cagcacaaaagttccaggga tggtgccaaa ctcactagaa 30116 ccgctcccga gtaacaaaac tgatgaatgggagtaacaca gtgtaaaatg tgcaaccaaa 30176 aatcactaag gtgctccttt aaaaagtccagtacttctat attcagtccg tgcaagtact 30236 gaagcaactg tgcgggaata tgcacaacaaaaaaaatagg gcggctcaga tacatgttga 30296 cctaaaataa aaagaatcat taaactaaagaagcttggcg aacggtggga taaatgacac 30356 gctccagcag cagacaggca accggctgtccccgggaacc gcggtaaaat tcatccgaat 30416 gattaaaaag aacaacagaa acttcccaccatgtactcgg ttggatctcc tgagcacaca 30476 gcaatacccc cctcacattc atgtccgccacagaaaaaaa acgtcccaga tacccagcgg 30536 ggatatccaa cgacagctgc aaagacagcaaaacaatccc tctgggagcg atcacaaaat 30596 cctccggtga aaaaagcaca tacatattagaataaccctg ttgctggggc aaaaaggccc 30656 ggcgtcccag caaatgcaca taaatatgttcatcagccat tgccccgtct taccgcgtaa 30716 tcagccacga aaaaatcgag ctaaaattcacccaacagcc tatagctata tatacactcc 30776 gcccaatgac gctaataccg caccacccacgaccaaagtt cacccacacc cacaaaaccc 30836 gcgaaaatcc agcgccgtca gcacttccgcaatttcagtc tcacaacgtc acttccgcgc 30896 gccttttcac attcccacac acacccgcgcccttcgcccc gccctcgcgc caccccgcgt 30956 caccgcacgt caccccggcc ccgcctcgctcctccccgct cattatcata ttggcacgtt 31016 tccagaataa ggtatattat tgatgatg31044 30 505 PRT simian adenovirus SV-25 30 Met Arg Arg Ala Val Arg ValThr Pro Ala Ala Tyr Glu Gly Pro Pro 1 5 10 15 Pro Ser Tyr Glu Ser ValMet Gly Ser Ala Asn Val Pro Ala Thr Leu 20 25 30 Glu Ala Pro Tyr Val ProPro Arg Tyr Leu Gly Pro Thr Glu Gly Arg 35 40 45 Asn Ser Ile Arg Tyr SerGlu Leu Ala Pro Leu Tyr Asp Thr Thr Lys 50 55 60 Val Tyr Leu Val Asp AsnLys Ser Ala Asp Ile Ala Ser Leu Asn Tyr 65 70 75 80 Gln Asn Asp His SerAsn Phe Leu Thr Thr Val Val Gln Asn Asn Asp 85 90 95 Phe Thr Pro Thr GluAla Gly Thr Gln Thr Ile Asn Phe Asp Glu Arg 100 105 110 Ser Arg Trp GlyGly Gln Leu Lys Thr Ile Leu His Thr Asn Met Pro 115 120 125 Asn Ile AsnGlu Phe Met Ser Thr Asn Lys Phe Arg Ala Lys Leu Met 130 135 140 Val GluLys Ser Asn Ala Glu Thr Arg Gln Pro Arg Tyr Glu Trp Phe 145 150 155 160Glu Phe Thr Ile Pro Glu Gly Asn Tyr Ser Glu Thr Met Thr Ile Asp 165 170175 Leu Met Asn Asn Ala Ile Val Asp Asn Tyr Leu Gln Val Gly Arg Gln 180185 190 Asn Gly Val Leu Glu Ser Asp Ile Gly Val Lys Phe Asp Thr Arg Asn195 200 205 Phe Arg Leu Gly Trp Asp Pro Val Thr Lys Leu Val Met Pro GlyVal 210 215 220 Tyr Thr Asn Glu Ala Phe His Pro Asp Ile Val Leu Leu ProGly Cys 225 230 235 240 Gly Val Asp Phe Thr Gln Ser Arg Leu Ser Asn LeuLeu Gly Ile Arg 245 250 255 Lys Arg Arg Pro Phe Gln Glu Gly Phe Gln IleMet Tyr Glu Asp Leu 260 265 270 Glu Gly Gly Asn Ile Pro Ala Leu Leu AspVal Ser Lys Tyr Glu Ala 275 280 285 Ser Ile Gln Arg Ala Lys Ala Glu GlyArg Glu Ile Arg Gly Asp Thr 290 295 300 Phe Ala Val Ala Pro Gln Asp LeuGlu Ile Val Pro Leu Thr Lys Asp 305 310 315 320 Ser Lys Asp Arg Ser TyrAsn Ile Ile Asn Asn Thr Thr Asp Thr Leu 325 330 335 Tyr Arg Ser Trp PheLeu Ala Tyr Asn Tyr Gly Asp Pro Glu Lys Gly 340 345 350 Val Arg Ser TrpThr Ile Leu Thr Thr Thr Asp Val Thr Cys Gly Ser 355 360 365 Gln Gln ValTyr Trp Ser Leu Pro Asp Met Met Gln Asp Pro Val Thr 370 375 380 Phe ArgPro Ser Thr Gln Val Ser Asn Phe Pro Val Val Gly Thr Glu 385 390 395 400Leu Leu Pro Val His Ala Lys Ser Phe Tyr Asn Glu Gln Ala Val Tyr 405 410415 Ser Gln Leu Ile Arg Gln Ser Thr Ala Leu Thr His Val Phe Asn Arg 420425 430 Phe Pro Glu Asn Gln Ile Leu Val Arg Pro Pro Ala Pro Thr Ile Thr435 440 445 Thr Val Ser Glu Asn Val Pro Ala Leu Thr Asp His Gly Thr LeuPro 450 455 460 Leu Arg Ser Ser Ile Ser Gly Val Gln Arg Val Thr Ile ThrAsp Ala 465 470 475 480 Arg Arg Arg Thr Cys Pro Tyr Val Tyr Lys Ala LeuGly Val Val Ala 485 490 495 Pro Lys Val Leu Ser Ser Arg Thr Phe 500 50531 921 PRT simian adenovirus SV-25 31 Met Ala Thr Pro Ser Met Met ProGln Trp Ser Tyr Met His Ile Ala 1 5 10 15 Gly Gln Asp Ala Ser Glu TyrLeu Ser Pro Gly Leu Val Gln Phe Ala 20 25 30 Arg Ala Thr Asp Thr Tyr PheSer Leu Gly Asn Lys Phe Arg Asn Pro 35 40 45 Thr Val Ala Pro Thr His AspVal Thr Thr Asp Arg Ser Gln Arg Leu 50 55 60 Thr Leu Arg Phe Val Pro ValAsp Arg Glu Asp Thr Ala Tyr Ser Tyr 65 70 75 80 Lys Val Arg Tyr Thr LeuAla Val Gly Asp Asn Arg Val Leu Asp Met 85 90 95 Ala Ser Thr Tyr Phe AspIle Arg Gly Val Leu Asp Arg Gly Pro Ser 100 105 110 Phe Lys Pro Tyr SerGly Thr Ala Tyr Asn Ser Leu Ala Pro Lys Gly 115 120 125 Ala Pro Asn ProSer Glu Trp Thr Asp Thr Ser Asp Asn Lys Leu Lys 130 135 140 Ala Tyr AlaGln Ala Pro Tyr Gln Ser Gln Gly Leu Thr Lys Asp Gly 145 150 155 160 IleGln Val Gly Leu Val Val Thr Glu Ser Gly Gln Thr Pro Gln Tyr 165 170 175Ala Asn Lys Val Tyr Gln Pro Glu Pro Gln Ile Gly Glu Asn Gln Trp 180 185190 Asn Leu Glu Gln Glu Asp Lys Ala Ala Gly Arg Val Leu Lys Lys Asp 195200 205 Thr Pro Met Phe Pro Cys Tyr Gly Ser Tyr Ala Arg Pro Thr Asn Glu210 215 220 Gln Gly Gly Gln Ala Lys Asn Gln Glu Val Asp Leu Gln Phe PheAla 225 230 235 240 Thr Pro Gly Asp Thr Gln Asn Thr Ala Lys Val Val LeuTyr Ala Glu 245 250 255 Asn Val Asn Leu Glu Thr Pro Asp Thr His Leu ValPhe Lys Pro Asp 260 265 270 Asp Asp Ser Thr Ser Ser Lys Leu Leu Leu GlyGln Gln Ala Ala Pro 275 280 285 Asn Arg Pro Asn Tyr Ile Gly Phe Arg AspAsn Phe Ile Gly Leu Met 290 295 300 Tyr Tyr Asn Ser Thr Gly Asn Met GlyVal Leu Ala Gly Gln Ala Ser 305 310 315 320 Gln Leu Asn Ala Val Val AspLeu Gln Asp Arg Asn Thr Glu Leu Ser 325 330 335 Tyr Gln Leu Met Leu AspAla Leu Gly Asp Arg Ser Arg Tyr Phe Ser 340 345 350 Met Trp Asn Gln AlaVal Asp Ser Tyr Asp Pro Asp Val Arg Ile Ile 355 360 365 Glu Asn His GlyVal Glu Asp Glu Leu Pro Asn Tyr Cys Phe Pro Leu 370 375 380 Gly Gly MetVal Val Thr Asp Asn Tyr Asn Ser Val Thr Pro Gln Asn 385 390 395 400 GlyGly Ser Gly Asn Thr Trp Gln Ala Asp Asn Thr Thr Phe Ser Gln 405 410 415Arg Gly Ala Gln Ile Gly Ser Gly Asn Met Phe Ala Leu Glu Ile Asn 420 425430 Leu Gln Ala Asn Leu Trp Arg Gly Phe Leu Tyr Ser Asn Ile Gly Leu 435440 445 Tyr Leu Pro Asp Ser Leu Lys Ile Thr Pro Asp Asn Ile Thr Leu Pro450 455 460 Glu Asn Lys Asn Thr Tyr Gln Tyr Met Asn Gly Arg Val Thr ProPro 465 470 475 480 Gly Leu Ile Asp Thr Tyr Val Asn Val Gly Ala Arg TrpSer Pro Asp 485 490 495 Val Met Asp Ser Ile Asn Pro Phe Asn His His ArgAsn Ala Gly Leu 500 505 510 Arg Tyr Arg Ser Met Leu Leu Gly Asn Gly ArgTyr Val Pro Phe His 515 520 525 Ile Gln Val Pro Gln Lys Phe Phe Ala IleLys Asn Leu Leu Leu Leu 530 535 540 Pro Gly Ser Tyr Thr Tyr Glu Trp AsnPhe Arg Lys Asp Val Asn Met 545 550 555 560 Ile Leu Gln Ser Ser Leu GlyAsn Asp Leu Arg Val Asp Gly Ala Ser 565 570 575 Ile Arg Phe Asp Ser IleAsn Leu Tyr Ala Asn Phe Phe Pro Met Ala 580 585 590 His Asn Thr Ala SerThr Leu Glu Ala Met Leu Arg Asn Asp Thr Asn 595 600 605 Asp Gln Ser PheAsn Asp Tyr Leu Cys Ala Ala Asn Met Leu Tyr Pro 610 615 620 Ile Pro AlaAsn Ala Thr Ser Val Pro Ile Ser Ile Pro Ser Arg Asn 625 630 635 640 TrpAla Ala Phe Arg Gly Trp Ser Phe Thr Arg Leu Lys Thr Lys Glu 645 650 655Thr Pro Ser Leu Gly Ser Gly Phe Asp Pro Tyr Phe Val Tyr Ser Gly 660 665670 Ser Ile Pro Tyr Leu Asp Gly Thr Phe Tyr Leu Asn His Thr Phe Lys 675680 685 Lys Val Ser Ile Met Phe Asp Ser Ser Val Ser Trp Pro Gly Asn Asp690 695 700 Arg Leu Leu Thr Pro Asn Glu Phe Glu Ile Lys Arg Ser Val AspGly 705 710 715 720 Glu Gly Tyr Asn Val Ala Gln Ser Asn Met Thr Lys AspTrp Phe Leu 725 730 735 Ile Gln Met Leu Ser His Tyr Asn Ile Gly Tyr GlnGly Phe Tyr Val 740 745 750 Pro Glu Asn Tyr Lys Asp Arg Met Tyr Ser PhePhe Arg Asn Phe Gln 755 760 765 Pro Met Ser Arg Gln Val Val Asp Thr ValThr Tyr Thr Asp Tyr Lys 770 775 780 Asp Val Lys Leu Pro Tyr Gln His AsnAsn Ser Gly Phe Val Gly Tyr 785 790 795 800 Met Gly Pro Thr Met Arg GluGly Gln Ala Tyr Pro Ala Asn Tyr Pro 805 810 815 Tyr Pro Leu Ile Gly GluThr Ala Val Pro Ser Leu Thr Gln Lys Lys 820 825 830 Phe Leu Cys Asp ArgVal Met Trp Arg Ile Pro Phe Ser Ser Asn Phe 835 840 845 Met Ser Met GlySer Leu Thr Asp Leu Gly Gln Asn Met Leu Tyr Ala 850 855 860 Asn Ser AlaHis Ala Leu Asp Met Thr Phe Glu Val Asp Pro Met Asp 865 870 875 880 GluPro Thr Leu Leu Tyr Val Leu Phe Glu Val Phe Asp Val Val Arg 885 890 895Ile His Gln Pro His Arg Gly Val Ile Glu Ala Val Tyr Leu Arg Thr 900 905910 Pro Phe Ser Ala Gly Asn Ala Thr Thr 915 920 32 347 PRT simianadenovirus SV-25 32 Met Lys Ile Cys Val Val Ile Phe Ala Leu Ser Leu IleLys Thr Glu 1 5 10 15 Leu Phe Ala Val Pro Ser Thr Pro Arg Val Val SerPro Cys Glu Lys 20 25 30 Thr Pro Gly Val Leu Asn Leu His Ile Ala Lys ProLeu Tyr Phe Thr 35 40 45 Ile Glu Lys Gln Leu Ala Leu Ser Ile Gly Lys GlyLeu Thr Ile Ser 50 55 60 Ala Thr Gly Gln Leu Glu Ser Thr Ala Ser Val GlnAsp Ser Ala Thr 65 70 75 80 Pro Pro Leu Arg Gly Ile Ser Pro Leu Lys LeuThr Asp Asn Gly Leu 85 90 95 Thr Leu Ser Tyr Ser Asp Pro Leu Arg Val ValGly Asp Gln Leu Thr 100 105 110 Phe Asn Phe Thr Ser Pro Leu Arg Tyr GluAsn Gly Ser Leu Thr Phe 115 120 125 Asn Tyr Thr Ser Pro Met Thr Leu IleAsn Asn Ser Leu Ala Ile Asn 130 135 140 Val Asn Thr Ser Lys Gly Leu SerSer Asp Asn Gly Thr Leu Ala Val 145 150 155 160 Asn Val Thr Pro Asp PheArg Phe Asn Ser Ser Gly Ala Leu Thr Phe 165 170 175 Gly Ile Gln Ser LeuTrp Thr Phe Pro Thr Lys Thr Pro Asn Cys Thr 180 185 190 Val Phe Thr GluSer Asp Ser Leu Leu Ser Leu Cys Leu Thr Lys Cys 195 200 205 Gly Ala HisVal Leu Gly Ser Val Ser Leu Ser Gly Val Ala Gly Thr 210 215 220 Met LeuLys Met Thr His Thr Ser Val Thr Val Gln Phe Ser Phe Asp 225 230 235 240Asp Ser Gly Lys Leu Ile Phe Ser Pro Leu Ala Asn Asn Thr Trp Gly 245 250255 Val Arg Gln Ser Glu Ser Pro Leu Pro Asn Pro Ser Phe Asn Ala Leu 260265 270 Thr Phe Met Pro Asn Ser Thr Ile Tyr Ser Arg Gly Ala Ser Asn Glu275 280 285 Pro Gln Asn Asn Tyr Tyr Val Gln Thr Tyr Leu Arg Gly Asn ValArg 290 295 300 Lys Pro Ile Leu Leu Thr Val Thr Tyr Asn Ser Val Asn SerGly Tyr 305 310 315 320 Ser Leu Thr Phe Lys Trp Asp Ala Val Ala Asn GluLys Phe Ala Thr 325 330 335 Pro Thr Ser Ser Phe Cys Tyr Val Ala Glu Gln340 345 33 559 PRT simian adenovirus SV-25 33 Met Lys Arg Ala Arg ValAsp Glu Asp Phe Asn Pro Val Tyr Pro Tyr 1 5 10 15 Asp Pro Pro Tyr AlaPro Val Met Pro Phe Ile Thr Pro Pro Phe Thr 20 25 30 Ser Ser Asp Gly LeuGln Glu Lys Pro Leu Gly Val Leu Ser Leu Asn 35 40 45 Tyr Arg Asp Pro IleThr Thr Gln Asn Gly Ser Leu Thr Leu Lys Leu 50 55 60 Gly Asn Gly Leu ThrLeu Asn Asn Gln Gly Gln Leu Thr Ser Thr Ala 65 70 75 80 Gly Glu Val GluPro Pro Leu Thr Asn Ala Asn Asn Lys Leu Ala Leu 85 90 95 Ala Tyr Ser GluPro Leu Ala Val Lys Ser Asn Arg Leu Thr Leu Ser 100 105 110 His Thr AlaPro Leu Val Ile Ala Asn Asn Ser Leu Ala Leu Gln Val 115 120 125 Ser GluPro Ile Phe Val Asn Asp Asp Asp Lys Leu Ala Leu Gln Thr 130 135 140 AlaAla Pro Leu Val Thr Asn Ala Gly Thr Leu Arg Leu Gln Ser Ala 145 150 155160 Ala Pro Leu Gly Leu Val Glu Asn Thr Leu Lys Leu Leu Phe Ser Lys 165170 175 Pro Leu Tyr Leu Gln Asn Asp Phe Leu Ala Leu Ala Ile Glu Arg Pro180 185 190 Leu Ala Val Ala Ala Ala Gly Thr Leu Thr Leu Gln Leu Thr ProPro 195 200 205 Leu Lys Thr Asn Asp Asp Gly Leu Thr Leu Ser Thr Val GluPro Leu 210 215 220 Thr Val Lys Asn Gly Asn Leu Gly Leu Gln Ile Ser ArgPro Leu Val 225 230 235 240 Val Gln Asn Asn Gly Leu Ser Leu Ala Ile ThrPro Pro Leu Arg Leu 245 250 255 Phe Asn Ser Asp Pro Val Leu Gly Leu GlyPhe Thr Phe Pro Leu Ala 260 265 270 Val Thr Asn Asn Leu Leu Ser Leu AsnMet Gly Asp Gly Val Lys Leu 275 280 285 Thr Tyr Asn Lys Leu Thr Ala AsnLeu Gly Arg Asp Leu Gln Phe Glu 290 295 300 Asn Gly Ala Ile Ala Val ThrLeu Thr Ala Glu Leu Pro Leu Gln Tyr 305 310 315 320 Thr Asn Lys Leu GlnLeu Asn Ile Gly Ala Gly Leu Arg Tyr Asn Gly 325 330 335 Ala Ser Arg LysLeu Asp Val Asn Ile Asn Gln Asn Lys Gly Leu Thr 340 345 350 Trp Asp AsnAsp Ala Val Ile Pro Lys Leu Gly Ser Gly Leu Gln Phe 355 360 365 Asp ProAsn Gly Asn Ile Ala Val Ile Pro Glu Thr Val Lys Pro Gln 370 375 380 ThrLeu Trp Thr Thr Ala Asp Pro Ser Pro Asn Cys Ser Val Tyr Gln 385 390 395400 Asp Leu Asp Ala Arg Leu Trp Leu Ala Leu Val Lys Ser Gly Asp Met 405410 415 Val His Gly Ser Ile Ala Leu Lys Ala Leu Lys Gly Thr Leu Leu Asn420 425 430 Pro Thr Ala Ser Tyr Ile Ser Ile Val Ile Tyr Phe Tyr Ser AsnGly 435 440 445 Val Arg Arg Thr Asn Tyr Pro Thr Phe Asp Asn Glu Gly ThrLeu Ala 450 455 460 Asn Ser Ala Thr Trp Gly Tyr Arg Gln Gly Gln Ser AlaAsn Thr Asn 465 470 475 480 Val Thr Asn Ala Thr Glu Phe Met Pro Ser SerSer Arg Tyr Pro Val 485 490 495 Asn Lys Gly Asp Asn Ile Gln Asn Gln SerPhe Ser Tyr Thr Cys Ile 500 505 510 Lys Gly Asp Phe Ala Met Pro Val ProPhe Arg Val Thr Tyr Asn His 515 520 525 Ala Leu Glu Gly Tyr Ser Leu LysPhe Thr Trp Arg Val Val Ala Asn 530 535 540 Gln Ala Phe Asp Ile Pro CysCys Ser Phe Ser Tyr Ile Thr Glu 545 550 555 34 34115 DNA simianadenovirus SV-39 CDS (13448)..(14959) L2 Penton 34 catcatcaat ataacaccgcaagatggcga ccgagttaac atgcaaatga ggtgggcgga 60 gttacgcgac ctttgtcttgggaacgcgga agtgggcgcg gcgggtttcg gggaggagcg 120 cggggcgggg cgggcgtgtcgcgcggcggt gacgcgccgg ggacccggaa attgagtagt 180 ttttattcat tttgcaagtttttctgtaca ttttggcgcg aaaactgaaa cgaggaagtg 240 aaaagtgaaa aatgccgaggtagtcaccgg gtggagatct gacctttgcc gtgtggagtt 300 tacccgctga cgtgtgggtttcggtctcta ttttttcact gtggttttcc gggtacggtc 360 aaaggtcccc attttatgactccacgtcag ctgatcgcta gggtatttaa tgcgcctcag 420 accgtcaaga ggccactcttgagtgccggc gagaagagtt ttctcctccg cgttccgcca 480 actgtgaaaa aatgaggaacttcttgctat ctccggggct gccagcgacc gtagccgccg 540 agctgttgga ggacattgttaccggagctc tgggagacga tcctcaggtg atttctcact 600 tttgtgaaga ttttagtcttcatgatctct atgatattga tccgggtgtt gaggggcaag 660 aggatgaatg gctggagtctgtggatgggt tttttccgga cgctatgctg ctagaggctg 720 atttgccacc acctcacaactctcacactg agcccgagtc agctgctatt cctgaattgt 780 catcaggtga acttgacttggcttgttacg agactatgcc tccggagtcg gatgaggagg 840 acagcgggat cagcgatcccacggctttta tggtctctaa ggcgattgct atactaaaag 900 aagatgatga tggcgatgatggatttcgac tggacgctcc ggcggtgccg gggagagact 960 gtaagtcctg tgaataccaccgggatcgta ccggagaccc gtctatgttg tgttctctgt 1020 gttatctccg tcttaacgctgcttttgtct acagtaagtg ttttgtgctt ttttaccctg 1080 tggctttgtt gagtttatttttttctgtgt ctcatagggt gttgtttatt ataggtcctg 1140 tttcagatgt ggaggaacctgatagtacta ctggaaatga ggaggaaaag ccctccccgc 1200 cgaaactaac tcagcgctgcagacctaata ttttgagacc ctcggcccag cgtgtgtcat 1260 cccggaaacg tgctgctgttaattgcatag aagatttatt ggaagagccc actgaacctt 1320 tggacttgtc cttaaagcgaccccgcccgc agtagggcgc ggtgccagtt ttttctctct 1380 agcttccggg tgactcagtgcaataaaaat tttcttggca acaggtgtat gtgtttactt 1440 tacgggcggg aagggattaggggagtataa agctggaggg gaaaaatctg aggctgtcag 1500 atcgagtgag aagttccatggacttgtacg agagcctaga gaatctaagt tctttgcgac 1560 gtttgctgga ggaggcctccgacagaacct cttacatttg gaggtttctg ttcggttccc 1620 ctctgagtcg ctttttgcaccgggtgaagc gagagcacct gacggaattt gatgggcttt 1680 tagagcagct gcctggactgtttgattctt tgaatctcgg ccaccggacg ctgctagagg 1740 agaggctttt tccacaattggacttttcct ctccaggccg tctgtgttca gcgcttgctt 1800 ttgctgtaca tctgttggacagatggaacg agcagacgca gctcagcccg ggttacactc 1860 tggacttcct gacgctatgcctatggaagt tcggaatcag gagggggagg aagctgtacg 1920 ggcgcttggt ggagaggcatccgtctctgc gccagcagcg tctgcaagct caagtgctgc 1980 tgaggcggga ggatctggaagccatttcgg aggaggagag cggcatggaa gagaagaatc 2040 cgagagcggg gctggaccctccggcggagg agtagggggg ataccggacc cttttcctga 2100 gttggctttg ggggcggtggggggcgcttc tgtggtacgt gaggatgaag aggggcgcca 2160 acgcggtcag aagagggagcattttgagtc ctcgactttc ttggctgatg taaccgtggc 2220 cctgatggcg aaaaacaggctggaggtggt gtggtacccg gaagtatggg aggactttga 2280 gaagggggac ttgcacctgctggaaaaata taactttgag caggtgaaaa catactggat 2340 gaacccggat gaggactgggaggtggtttt gaaccgatac ggcaaggtag ctctgcgtcc 2400 cgactgtcgc taccaggttcgcgacaaggt ggtcctgcga cgcaacgtgt acctgttggg 2460 caacggcgcc accgtggagatggtggaccc cagaaggggt ggttttgtgg ccaatatgca 2520 agaaatgtgc cctggggtggtgggcttgtc tggggtgact tttcatagtg tgaggtttag 2580 cggtagcaat tttgggggtgtggttattac cgcgaacact cctgtggtcc tgcataattg 2640 ctactttttt ggcttcagcaacacctgtgt ggaaatgagg gtgggaggca aagtgcgcgg 2700 gtgttccttt tacgcttgctggaagggggt ggtgagccag ggtaaggcta aagtgtctgt 2760 tcacaagtgt atgttggagagatgcacctt gggcatttcc agtgagggct tcctccacgc 2820 cagcgacaac gtggcttctgacaacggctg cgcctttctt atcaagggag ggggtcgcat 2880 ctgtcacaac atgatatgcggccctgggga tgtcccccca aagccttacc agatggttac 2940 ctgcacagat ggcaaggtgcgcatgctcaa gcctgtgcac attgtgggcc accggcgcca 3000 ccgctggcca gagtttgaacacaatgtgat gacccgctgt agcttgtacc tgggaggcag 3060 gcgaggagtt ttcttgcccagacagtgtaa cctggcccac tgcaacgtga tcatggaaca 3120 atccgccgct acccaggtttgctttggagg aatatttgat ataagcatgg tggtgtataa 3180 gatcctgcgc tacgacgactgtcgggctcg tactcgaacc tgcgactgcg gagcctctca 3240 cctgtgtaac ctgactgtgatggggatggt gactgaggag gtgcgactgg accactgtca 3300 gcactcttgc ctgcgggaggagttttcttc ctcggacgag gaggactagg taggtggttg 3360 gggcgtggcc agcgagagggtgggctataa aggggaggtg tcggctgacg ctgtcttctg 3420 tttttcaggt accatgagcggatcaagcag ccagaccgcg ctgagcttcg acggggccgt 3480 gtacagcccc tttctgacggggcgcttgcc tgcctgggcc ggagtgcgtc agaatgttac 3540 cggttcgacc gtggacggacgtcccgtgga tccatctaac gctgcttcta tgcgctacgc 3600 tactatcagc acatctactctggacagcgc cgctgccgcc gcagccgcca cctcagccgc 3660 tctctccgcc gccaagatcatggctattaa cccaagcctt tacagccctg tatccgtgga 3720 cacctcagcc ctggagctttaccggcgaga tctagctcaa gtggtggacc aactcgcagc 3780 cgtgagccaa cagttgcagctggtgtcgac ccgagtggag caactttccc gccctcccca 3840 gtaaccgcaa aaattcaataaacagaattt aataaacagc acttgagaaa agtttaaact 3900 tgtggttgac tttattcctggatagctggg gggagggaac ggcgggaacg gtaagacctg 3960 gtccatcgtt cccggtcgttgagaacacgg tggatttttt ccaagacccg atagaggtgg 4020 gtctgaacgt tgagatacatgggcatgagc ccgtctcggg ggtggaggta ggcccactgc 4080 agggcctcgt tttcaggggtggtgttgtaa atgatccagt cgtaggcccc ccgctgggcg 4140 tggtgctgga agatgtccttcagcagcaag ctgatggcaa cgggaagacc cttggtgtag 4200 gtgttgacaa agcggttgagttgggagggg tgcatgcggg gactgatgag gtgcattttg 4260 gcctggatct tgaggttggctatgttgccg cccagatcgc gcctgggatt catgttatgc 4320 aagaccacca gcaccgagtaaccggtgcag cgggggaatt tgtcgtgcag cttggaaggg 4380 aaagcgtgga agaatttggagacccctcgg tgcccgccta ggttttccat gcactcatcc 4440 atgatgatgg cgatgggcccccgggaggca gcctgggcaa aaacgttgcg ggggtccgtg 4500 acatcgtagt tgtggtcctgggtgagttca tcataggaca ttttgacaaa gcgcgggcag 4560 agggtcccag actggggaatgatggttcca tccggtccgg gggcgtagtt gccctcgcag 4620 atttgcattt cccaggctttgatttcagag ggagggatca tgtcaacctg gggggcgatg 4680 aaaaaaatgg tctctggggcgggggtgatg agctgggtgg aaagcaggtt gcgcaagagc 4740 tgtgacttgc cgcagccggtgggcccgtag atgacagcta tgacgggttg cagggtgtag 4800 tttagagagc tacaactgccatcatccttc aaaagcgggg ccacactgtt taaaagttct 4860 ctaacatgta agttttcccgcactaagtcc tgcaggagac gtgaccctcc tagggagaga 4920 agttcaggaa gcgaagcaaagtttttaagt ggcttgaggc catcggccaa gggcaagttc 4980 ctgagagttt gactgagcagttccagccgg tcccagagct cggttacgtg ctctacggca 5040 tctcgatcca gcagacctcctcgtttcggg ggttggggcg gctctggctg tagggaatga 5100 ggcggtgggc gtccagctgggccatggtgc ggtccctcca tgggcgcagg gttctcttca 5160 gggtggtctc ggtcacggtgaatgggtggg ccccgggctg ggcgctggcc agggtgcgct 5220 tgaggctgag gcggctggtggcgaaccgtt gcttttcgtc tccctgcaag tcagccaaat 5280 agcaacggac catgagctcatagtccaggc tctctgcggc atgtcctttg gcgcgaagct 5340 tgcctttgga aacgtgcccgcagtttgagc agagcaagca ttttagcgcg tagagttttg 5400 gcgccaagaa cacggattccggggaataag catccccacc gcagttggag caaacggttt 5460 cgcattccac cagccaggtcagctgaggat cttttgggtc aaaaaccaag cgcccgccgt 5520 tttttttgat gcgcttcctacctcgggtct ccatgaggcg gtgcccgcgt tcggtgacga 5580 agaggctgtc ggtgtctccgtagacggagg tcagggcgcg ctcctccagg ggggtcccgc 5640 ggtcctcggc gtagagaaactcgcaccact ctgacataaa cgcccgggtc caggctagga 5700 cgaatgaggc gatgtgggaagggtaccggt cgttatcgat gagggggtcg gttttttcca 5760 aggtgtgcag gcacatgtccccctcgtccg cttccaaaaa tgtgattggc ttgtaggtgt 5820 aagtcacgtg atcctgtccttccgcggggg tataaaaggg ggcgtttccc ccctcctcgt 5880 cactctcttc cggttcgctgtcgccaaagg ccagctgttg gggtacgtaa acgcgggtga 5940 aggcgggcat gacctgtgcgctgaggttgt cagtttctat atacgaggaa gatttgatgg 6000 cgagcgcccc cgtggagatgcccttgaggt gctcggggcc catttggtca gaaaacacaa 6060 tctgtcggtt atcaagcttggtggcaaaag acccgtagag ggcgttggag agcaacttgg 6120 cgatggagcg ctgggtttggtttttttccc ggtcggcttt ttccttggcc gcgatgttga 6180 gctggacgta ctccctggccacgcacttcc agccgggaaa aacggccgtg cgctcgtccg 6240 gcaccagcct cacgctccatccgcggttgt gcagggtgat gacgtcgatg ctggtggcca 6300 cctctccgcg caggggctcgttggtccagc agaggcgacc gcccttgcga gagcagaagg 6360 ggggcagggg gtcaagcaggcgctcgtccg gggggtcggc gtcgatggta aagatggcgg 6420 gcagcaggtg tttgtcaaagtaatcgatct gatgcccggg gcaacgcagg gcggtttccc 6480 agtcccgcac cgccaaggcgcgctcgtatg gactgagggg ggcgccccag ggcatgggat 6540 gcgtcagggc cgaggcgtacatgccgcaga tgtcatagac gtaaaggggc tcctccagga 6600 cgccgaggta ggtggggtagcagcgccccc cgcggatgct ggcccgtacg tagtcgtaga 6660 gctcgtgcga gggggccagaaggtggcggc tgaggtgagc gcgctggggc ttttcatctc 6720 ggaagaggat ctgcctgaagatggcgtggg agttggagga gatggtgggc cgctgaaaaa 6780 tgttgaagcg ggcgtcgggcagacccacgg cctcgccgat aaagtgggcg taggactctt 6840 gcagcttttc caccagggaggcggtgacca gcacgtccag agcgcagtag tccagggttt 6900 cccgcacgat gtcataatgctcttcctttt tttccttcca gaggtctcgg ttgaagagat 6960 actcttcgcg gtctttccagtactcttgga gaggaaaccc gttttcgtct ccacggtaag 7020 agcccaacat gtaaaactggttgacggcct gatagggaca gcatcccttc tccacgggca 7080 gcgagtaggc cagggcggccttgcgcaggg aggtgtgagt cagggcaaag gtgtcgcgga 7140 ccataacttt tacaaactggtacttaaagt cccggtcgtc gcacatgcct cgctcccagt 7200 ctgagtagtc tgtgcgctttttgtgcttgg ggttaggcag ggagtaggtg acgtcgttaa 7260 agaggatttt gccacatctgggcataaagt tgcgagagat tctgaagggg ccgggcacct 7320 ccgagcggtt gttgatgacttgggcagcca ggagaatttc gtcgaagccg ttgatgttgt 7380 gccccacgac gtagaactctatgaaacgcg gagcgccgcg cagcaggggg cacttttcaa 7440 gttgctggaa agtaagttcccgcggctcga cgccgtgttc cgtgcggctc cagtcctcca 7500 ccgggtttcg ctccacaaaatcctgccaga tgtggtcgac tagcaagagc tgcagtcggt 7560 cgcgaaattc gcggaattttctgccgatgg cttgcttctg ggggttcaag caaaaaaagg 7620 tgtctgcgtg gtcgcgccaggcgtcccagc cgagctcgcg agccagattc agggccagca 7680 gcaccagagc cggctcaccggtgattttca tgacgaggag aaagggcacc agctgttttc 7740 cgaacgcgcc catccaggtgtaggtctcca cgtcgtaggt gagaaacaga cgttcggtcc 7800 gcgggtgcga tcccagggggaaaaacttga tgggctgcca ccattgggag ctctgggcgt 7860 ggatgtgatg gaagtaaaagtcccggcggc gcgtggaaca ttcgtgctgg tttttgtaaa 7920 agcggccgca gtggtcgcagcgcgagacgg agtgaaggct gtgaatcagg tgaatcttgc 7980 gtcgctgagg gggccccagagccaaaaagc ggagcgggaa cgaccgcgcg gccacttcgg 8040 cgtccgcagg caagatggatgagggttcca ccgttccccg cccgcggacc gaccagactt 8100 ccgccagctg cggcttcagttcttgcacca gctctcgcag cgtttcgtcg ctgggcgaat 8160 cgtgaatacg gaagttgtcgggtagaggcg ggaggcggtg gacttccagg aggtgtgtga 8220 gggccggcag gagatgcaggtggtacttga tttcccacgg atgacggtcg cgggcgtcca 8280 aggcgaagag atgaccgtggggccgcggcg ccaccagcgt tccgcggggg gtctttatcg 8340 gcggcgggga cgggctcccggcggcagcgg cggctcggga cccgcgggca agtcgggcag 8400 cggcacgtcg gcgtggagctcgggcagggg ctggtgctgc gcgcggagct gactggcaaa 8460 ggctatcacc cggcgattgacgtcctggat ccggcggcgc tgcgtgaaga ccaccggacc 8520 cgtggtcttg aacctgaaagagagttcgac agaatcaatc tcggcatcgt taaccgcggc 8580 ctggcgcagg atttcggccacgtccccgga gttgtcttga tacgcgattt ctgccatgaa 8640 ctggtcgatt tcctcttcctgcaagtctcc gtgaccggcg cgttcgacgg tggccgcgag 8700 atcgttggag atgcggcccatgagctggga aaaggcattg atgccgacct cgttccacac 8760 tcggctgtac accacctctccgtgaacgtc gcgggcgcgc atcaccacct gggcgagatt 8820 gagttccacg tggcgggcgaaaaccggata gtttcggagg cgctgataca gatagttgag 8880 ggtggtggcg gcgtgctcggccacaaaaaa atacatgatc cagcggcgga gggtcagctc 8940 gttgatgtcg cccagcgcctccaggcgttc catggcctcg taaaagtcca cggcaaagtt 9000 gaaaaattgg ctgttcctggccgagaccgt gagctcttct tccaagagcc gaatgagatc 9060 cgccacggtg gccctgacttcgcgttcgaa agccccgggt gcctcctcca cctcttcctc 9120 ctcgacttct tcgaccgcttcgggcacctc ctcttcctcg accaccacct caggcggggc 9180 tcggcggcgc cggcggcggacgggcaggcg gtcgacgaaa cgctcgatca tttcccccct 9240 ccgtcgacgc atggtctcggtgacggcgcg accctgttcg cgaggacgca gggtgaaggc 9300 gccgccgccg agcggaggtaacagggagat cggggggcgg tcgtggggga gactgacggc 9360 gctaactatg catctgatcaatgtttgcgt agtgacctcg ggtcggagcg agctcagcgc 9420 ttgaaaatcc acgggatcggaaaaccgttc caggaacgcg tctagccaat cacagtcgca 9480 aggtaagctg aggaccgtctcgggggcttg tctgttctgt cttcccgcgg tggtgctgct 9540 gatgaggtag ttgaagtaggcgctcttgag gcggcggatg gtggacagga gaaccacgtc 9600 tttgcgccca gcttgctgtatccgcaggcg gtcggccatg ccccacactt ctccttgaca 9660 gcggcggagg tccttgtagtattcttgcat cagcctttcc acgggcacct cgtcttcttc 9720 ttccgctcgg ccggacgagagccgcgtcag gccgtacccg cgctgcccct gtggttggag 9780 cagggccagg tcggccacgacgcgctcggc cagcacggcc tgctggatgc gggtgagggt 9840 gtcctgaaag tcgtcgagatccacaaagcg gtggtacgcg ccagtgttga tggtgtaggt 9900 gcagttgctc atgacggaccagtttacggt ctgggtgcca tggcccacgg tttccaggta 9960 gcggagacgc gagtaggcccgcgtctcgaa gatgtagtcg ttgcaggtcc gcagcaggta 10020 ctggtagccc accagcagatgcggcggcgg ctggcggtag aggggccacc gctgggtggc 10080 gggggcgttg ggggcgagatcttccaacat gaggcggtga tagccgtaga tgtagcgcga 10140 catccaagtg atgccgctggccgtggtgct ggcgcgggcg tagtcgcgaa cgcggttcca 10200 gatgtttcgc agcggctggaagtactcgat ggtggggcga ctctgccccg tgaggcgggc 10260 gcagtcggcg atgctctacggggaaaaaga agggccagtg aacaaccgcc ttccgtagcc 10320 ggaggagaac gcaagggggtcaaagaccac cgaggctcgg gttcgaaacc cgggtggcgg 10380 cccgaatacg gagggcggttttttgctttt ttctcagatg catcccgtgc tgcggcagat 10440 gcgtccgaac gcggggtcccagtccccggc ggtgcctgcg gccgtgacgg cggcttctac 10500 ggccacgtcg cgctccaccccgcctaccac ggcccaggcg gcggtggctc tgcgcggcgc 10560 aggggaaccc gaagcagaggcggtgttgga cgtggaggag ggccaggggt tggctcggct 10620 gggggccctg agtcccgagcggcacccgcg cgtggctctg aagcgcgacg cggcggaggc 10680 gtacgtgccg cggagcaatctgtttcgcga ccgcagcggc gaggaggccg aggagatgcg 10740 agacttgcgt tttcgggcggggagggagtt gcgtcacggg ctggaccggc agagggttct 10800 gagagaggag gactttgaggcggacgagcg cacgggggtg agtcccgcgc gggctcacgt 10860 ggcggccgcc aacctggtgagcgcgtacga gcagacggtc aaggaggaga tgaacttcca 10920 gaagagcttc aatcatcacgtgcgcacgct gattgcgcgc gaagaggtgg ccatcggcct 10980 catgcatctg tgggattttgtggaggcgta cgttcagaac cccagcagca agccgctgac 11040 ggctcagctg ttcctcatcgtgcaacatag tcgagacaac gaaacgttca gggaggccat 11100 gctgaacatt gcagagcctgaggggcgctg gctcttggat ctcattaaca tcttgcagag 11160 tatcgtagtg caggagcgctcgctgagcct ggccgacaag gtggctgcca tcaactacag 11220 catgctgtcg ctgggcaaattttacgcccg caagatctac aagtctccgt tcgtccccat 11280 agacaaggag gtgaagatagacagctttta catgcgcatg gcgctcaagg tgctgactct 11340 aagcgacgac ctgggggtgtaccgcaacga ccgcatacac aaggcggtga gcgccagccg 11400 ccggcgcgag ctgagcgaccgcgagctttt gcacagcctg catcgggcgt tgactggtgc 11460 cggcagcgcc gaggcggccgagtactttga cgccggagcg gacttgcgct ggcagccatc 11520 ccgacgcgcg ctggaggcggctggcgtcgg ggagtacggg gtcgaggacg acgatgaagc 11580 ggacgacgag ttgggcattgacttgtagcc gtttttcgtt agatatgtcg gcgaacgagc 11640 cgtctgcggc cgccatggtgacggcggcgg gcgcgcccca ggacccggcc acgcgcgcgg 11700 cgctgcagag tcagccttccggagtgacgc ccgcggacga ctggtccgag gccatgcgtc 11760 gcatcctggc gctgacggcgcgcaaccccg aggcttttcg gcagcagccg caggcaaacc 11820 ggtttgcggc cattttggaagcggtggtgc cctccagacc caaccccacc cacgaaaagg 11880 tgctggccat cgtcaacgccctggcggaga ccaaggccat ccgcccagac gaggccgggc 11940 aggtttacaa cgcgctgctagaaagggtgg gacgctacaa cagctccaac gtgcagacca 12000 atctggaccg cttggtgacggacgtgaagg aggccgtagc ccagcgagag cggtttttca 12060 aggaagccaa tctgggctcgctggtggccc tcaacgcctt cctgagcacg ctgccggcga 12120 acgtgccccg cggtcaggaggactacgtga actttctgag cgccctccgc ctgatggtgg 12180 ccgaggtgcc gcagagcgaggtgtaccagt ctggccccaa ctactacttc cagacctccc 12240 ggcagggcct gcagacggtaaacctgacgc aggcctttca gaacctgcag ggcctttggg 12300 gggtgcgcgc tccgctgggcgaccgcagca cggtgtccag cctgctgacc cccaatgccc 12360 ggctgctctt gcttctcattgctccgttca ccgacagcgg ttccatcagc cgcgactctt 12420 acctgggaca cctgctcaccctgtaccggg aggccatcgg gcaggcgcgg gtggacgagc 12480 agacgtacca ggaaatcaccagcgtgagcc gcgcgctggg gcaggaggac acgggcagct 12540 tggaggcgac tctgaacttcctgctgacca accggcggca gcgcctacct ccccagtacg 12600 cgctgaacgc ggaggaggagcgcatcctgc gtttcgtgca gcagagcacc gcgctgtact 12660 tgatgcggga aggcgcctctcccagcgctt cgctggacat gacggcggcc aacatggagc 12720 catcgttcta cgccgccaaccgtcccttcg tcaaccggct aatggactat ttgcatcggg 12780 cggcggccct gaacccggaatactttacta acgtcatcct gaacgaccgt tggctgccac 12840 ctcccggctt ctacacgggggagttcgacc tcccggaggc caacgacggt ttcatgtggg 12900 acgacgtgga cagcgtgttcctgcccggca agaaggaggc gggtgactct cagagccacc 12960 gcgcgagcct cgcagacctgggggcgaccg ggcccgcgtc tccgctgcct cgcctgccga 13020 gcgccagcag cgccagcgtggggcgggtga gccgtccgcg cctcagcggt gaggaggact 13080 ggtggaacga tccgctgctccgtccggccc gcaacaaaaa cttccccaac aacgggatag 13140 aggatttggt agacaaaatgaaccgttgga agacgtatgc ccaggagcat cgggagtggc 13200 aggcgaggca acccatgggccctgttctgc cgccctctcg gcgcccgcgc agggacgaag 13260 acgccgacga ttcagccgatgacagcagcg tgttggatct gggcgggagc gggaacccct 13320 ttgcccacct gcaacctcgcggcgtgggtc ggcggtggcg ctaggaaaaa aaattattaa 13380 aagcacttac cagagccatggtaagaagag caacaaaggt gtgtcctgct ttcttcccgg 13440 tagcaaa atg cgt cgggcg gtg gca gtt ccc tcc gcg gca atg gcg tta 13489 Met Arg Arg Ala ValAla Val Pro Ser Ala Ala Met Ala Leu 1 5 10 ggc ccg ccc cct tct tac gaaagc gtg atg gca gcg gcc acc ctg caa 13537 Gly Pro Pro Pro Ser Tyr GluSer Val Met Ala Ala Ala Thr Leu Gln 15 20 25 30 gcg ccg ttg gag aat ccttac gtg ccg ccg cga tac ctg gag cct acg 13585 Ala Pro Leu Glu Asn ProTyr Val Pro Pro Arg Tyr Leu Glu Pro Thr 35 40 45 ggc ggg aga aac agc attcgt tac tcg gag ctg acg ccc ctg tac gac 13633 Gly Gly Arg Asn Ser IleArg Tyr Ser Glu Leu Thr Pro Leu Tyr Asp 50 55 60 acc acc cgc ctg tac ctggtg gac aac aag tca gca gat atc gcc acc 13681 Thr Thr Arg Leu Tyr LeuVal Asp Asn Lys Ser Ala Asp Ile Ala Thr 65 70 75 ttg aac tac cag aac gaccac agc aac ttt ctc acg tcc gtg gtg cag 13729 Leu Asn Tyr Gln Asn AspHis Ser Asn Phe Leu Thr Ser Val Val Gln 80 85 90 aac agc gac tac acg cccgcc gaa gcg agc acg cag acc att aac ttg 13777 Asn Ser Asp Tyr Thr ProAla Glu Ala Ser Thr Gln Thr Ile Asn Leu 95 100 105 110 gac gac cgc tcgcgc tgg ggc ggg gac ttg aaa acc att ctg cac act 13825 Asp Asp Arg SerArg Trp Gly Gly Asp Leu Lys Thr Ile Leu His Thr 115 120 125 aac atg cccaac gtg aac gag ttc atg ttt acc aac tcg ttc agg gct 13873 Asn Met ProAsn Val Asn Glu Phe Met Phe Thr Asn Ser Phe Arg Ala 130 135 140 aaa cttatg gtg gcg cac gag gcc gac aag gac ccg gtt tat gag tgg 13921 Lys LeuMet Val Ala His Glu Ala Asp Lys Asp Pro Val Tyr Glu Trp 145 150 155 gtgcag ctg acg ctg ccg gag ggg aac ttt tca gag att atg acc ata 13969 ValGln Leu Thr Leu Pro Glu Gly Asn Phe Ser Glu Ile Met Thr Ile 160 165 170gac ctg atg aac aac gcc att atc gac cac tac ctg gcg gta gcc aga 14017Asp Leu Met Asn Asn Ala Ile Ile Asp His Tyr Leu Ala Val Ala Arg 175 180185 190 cag cag ggg gtg aaa gaa agc gag atc ggc gtc aag ttt gac acg cgc14065 Gln Gln Gly Val Lys Glu Ser Glu Ile Gly Val Lys Phe Asp Thr Arg195 200 205 aac ttt cgt ctg ggc tgg gac ccg gag acg ggg ctt gtg atg ccgggg 14113 Asn Phe Arg Leu Gly Trp Asp Pro Glu Thr Gly Leu Val Met ProGly 210 215 220 gtg tac acg aac gaa gct ttc cat ccc gac gtg gtc ctc ttgccg ggc 14161 Val Tyr Thr Asn Glu Ala Phe His Pro Asp Val Val Leu LeuPro Gly 225 230 235 tgc ggg gtg gac ttt acc tac agc cgg tta aac aac ctgcta ggc ata 14209 Cys Gly Val Asp Phe Thr Tyr Ser Arg Leu Asn Asn LeuLeu Gly Ile 240 245 250 cgc aag aga atg ccc ttt cag gaa ggg ttt cag atcctg tac gag gac 14257 Arg Lys Arg Met Pro Phe Gln Glu Gly Phe Gln IleLeu Tyr Glu Asp 255 260 265 270 ctg gag ggc ggt aac atc ccg gcc ctg ctggac gtg ccg gcg tac gag 14305 Leu Glu Gly Gly Asn Ile Pro Ala Leu LeuAsp Val Pro Ala Tyr Glu 275 280 285 gag agc atc gcc aac gca agg gag gcggcg atc agg ggc gat aat ttc 14353 Glu Ser Ile Ala Asn Ala Arg Glu AlaAla Ile Arg Gly Asp Asn Phe 290 295 300 gcg gcg cag ccc cag gcg gct ccaacc ata aaa ccc gtt ttg gaa gac 14401 Ala Ala Gln Pro Gln Ala Ala ProThr Ile Lys Pro Val Leu Glu Asp 305 310 315 tcc aaa ggg cgg agc tac aacgta ata gcc aac acc aac aac acg gct 14449 Ser Lys Gly Arg Ser Tyr AsnVal Ile Ala Asn Thr Asn Asn Thr Ala 320 325 330 tac agg agc tgg tat ctggct tat aac tac ggc gac ccg gag aag ggg 14497 Tyr Arg Ser Trp Tyr LeuAla Tyr Asn Tyr Gly Asp Pro Glu Lys Gly 335 340 345 350 gtt agg gcc tggacc ctg ctc acc act ccg gac gtg acg tgc ggt tca 14545 Val Arg Ala TrpThr Leu Leu Thr Thr Pro Asp Val Thr Cys Gly Ser 355 360 365 gag cag gtctac tgg tcg ctg cct gac atg tac gtg gac cct gtg acg 14593 Glu Gln ValTyr Trp Ser Leu Pro Asp Met Tyr Val Asp Pro Val Thr 370 375 380 ttt cgctcc acg cag caa gtt agc aac tac cca gtg gtg gga gcg gag 14641 Phe ArgSer Thr Gln Gln Val Ser Asn Tyr Pro Val Val Gly Ala Glu 385 390 395 cttatg ccg att cac agc aag agc ttt tac aac gag cag gcc gtc tac 14689 LeuMet Pro Ile His Ser Lys Ser Phe Tyr Asn Glu Gln Ala Val Tyr 400 405 410tca cag ctc att cgt cag acc acc gcc cta acg cac gtt ttc aac cgc 14737Ser Gln Leu Ile Arg Gln Thr Thr Ala Leu Thr His Val Phe Asn Arg 415 420425 430 ttc ccc gag aac caa atc cta gtg cga cct cca gcg ccc acc atc acc14785 Phe Pro Glu Asn Gln Ile Leu Val Arg Pro Pro Ala Pro Thr Ile Thr435 440 445 acc gtc agc gag aac gtg ccc gct cta acc gat cac ggg acg ctgcct 14833 Thr Val Ser Glu Asn Val Pro Ala Leu Thr Asp His Gly Thr LeuPro 450 455 460 ttg cag aac agc atc cgc gga gtt cag cga gtt acc atc acggac gcc 14881 Leu Gln Asn Ser Ile Arg Gly Val Gln Arg Val Thr Ile ThrAsp Ala 465 470 475 cgt cgt cgg acc tgt ccc tac gtc tac aaa gcc ttg ggaatc gtg gcc 14929 Arg Arg Arg Thr Cys Pro Tyr Val Tyr Lys Ala Leu GlyIle Val Ala 480 485 490 ccg cgc gtc ctg tcg agt cgc act ttc tagatgtccatcc tcatctctcc 14979 Pro Arg Val Leu Ser Ser Arg Thr Phe 495 500cagcaacaat accggttggg gtctgggcgt gaccaaaatg tacggaggcg ccaaacgacg 15039gtccccacaa catcccgtgc gagtgcgcgg gcactttaga gccccatggg ggtcgcacac 15099gcgcgggcgc accggccgaa ccaccgtcga cgacgtgatc gatagcgtgg tggccgacgc 15159ccgcaactac cagcccgctc gatccacggt ggacgaagtc atcgacggcg tggtggccga 15219cgccagggcc tacgcccgca gaaagtctcg tctgcgccgc cgccgttcgc taaagcgccc 15279cacggccgcc atgaaagccg ctcgctctct gctgcgtcgc gcacgtatcg tgggtcgccg 15339cgccgccaga cgcgcagccg ccaacgccgc cgccggccga gtgcgccgcc gggccgccca 15399gcaggccgcc gccgccatct ccagtctatc cgccccccga cgcgggaatg tgtactgggt 15459cagggactcg gccaccggcg tgcgagttcc cgtgagaacc cgtcctcctc gtccctgaat 15519aaaaagttct aagcccaatc ggtgttccgt tgtgtgttca gctcgtcatg accaaacgca 15579agtttaaaga ggagctgctg caagcgctgg tccccgaaat ctatgcgccg gcgccggacg 15639tgaaaccgcg tcgcgtgaaa cgcgtgaaga agcaggaaaa gctagagaca aaagaggagg 15699cggtggcgtt gggagacggg gaggtggagt ttgtgcgctc gttcgcgccg cgtcggcgag 15759tgaattggaa ggggcgcaag gtgcaacggg tgctgcgtcc cggcacggtg gtgtctttca 15819ccccgggtga aaaatccgcc tggaagggca taaagcgcgt gtacgatgag gtgtacgggg 15879acgaagacat tctggagcag gcgctggata gaagcgggga gtttgcttac ggcaagaggg 15939cgaggacggg cgagatcgcc atcccgctgg acacttccaa ccccaccccc agtctgaaac 15999ccgtgacgct gcaacaggtg ttgccggtga gcgccccctc gcgacgcggc ataaaacgcg 16059agggcggcga gctgcagccc accatgcagc tcctggttcc caagaggcag aaactagagg 16119acgtactgga catgataaaa atggagcccg acgtgcagcc cgatattaaa atccgtccca 16179tcaaagaagt ggcgccggga atgggcgtgc agaccgtgga catccagatt cccatgacca 16239gcgccgcaca ggcggtagag gccatgcaga ccgacgtggg gatgatgacg gacctgcccg 16299cagctgctgc cgccgtggcc agcgccgcga cgcaaacgga agccggcatg cagaccgacc 16359cgtggacgga ggcgcccgtg cagccggcca gaagacgcgt cagacggacg tacggccccg 16419tttctggcat aatgccggag tacgcgctgc atccttccat catccccacc cccggctacc 16479gggggcgcac ctaccgtccg cgacgcagca ccactcgccg ccgtcgccgc acggcacgag 16539tcgccaccgc cagagtgaga cgcgtaacga cacgtcgcgg ccgccgcttg accctgcccg 16599tggtgcgcta ccatcccagc attctttaaa aaaccgctcc tacgttgcag atgggcaagc 16659ttacttgtcg actccgtatg gccgtgcccg gctaccgagg aagatcccgc cgacgacgga 16719ctttgggagg cagcggtttg cgccgccgtc gggcggttca ccggcgcctc aagggaggca 16779ttctgccggc cctgatcccc ataatcgccg cagccatcgg ggccattccc ggaatcgcca 16839gcgtagcggt gcaggctagc cagcgccact gattttacta accctgtcgg tcgcgccgtc 16899tctttcggca gactcaacgc ccagcatgga agacatcaat ttctcctctc tggccccgcg 16959gcacggcacg cggccgtata tggggacgtg gagcgagatc ggcacgaacc agatgaacgg 17019gggcgctttc aattggagcg gtgtgtggag cggcttgaaa aatttcggtt ccactctgaa 17079aacttacggc aaccgggtgt ggaactccag cacggggcag atgctgaggg acaagctaaa 17139ggacacgcag tttcagcaaa aggtggtgga cggcatcgct tcgggcctca acggcgccgt 17199cgacctggcc aaccaggcca ttcaaaagga aattaacagc cgcctggagc cgcggccgca 17259ggtggaggag aacctgcccc ctctggaggc gctgcccccc aagggagaga agcgcccgcg 17319gcccgacatg gaggagacgc tagttactaa gagcgaggag ccgccatcat acgaggaggc 17379ggtgggtagc tcgcagctgc cgtccctcac gctgaagccc accacctatc ccatgaccaa 17439gcccatcgcc tccatggcgc gccccgtggg agtcgacccg cccatcgacg cggtggccac 17499tttggacctg ccgcgccccg aacccggcaa ccgcgtgcct cccgtcccca tcgctccgcc 17559ggtttctcgc cccgccatcc gccccgtcgc cgtggccact ccccgctatc cgagccgcaa 17619cgccaactgg cagaccaccc tcaacagtat tgtcggactg ggggtgaagt ctctgaagcg 17679ccgtcgctgt ttttaaagca caatttatta aacgagtagc cctgtcttaa tccatcgttg 17739tatgtgtgcc tatatcacgc gttcagagcc tgaccgtccg tcaag atg gcc act ccg 17796Met Ala Thr Pro 505 tcg atg atg ccg cag tgg tcg tac atg cac atc gcc gggcag gac gcc 17844 Ser Met Met Pro Gln Trp Ser Tyr Met His Ile Ala GlyGln Asp Ala 510 515 520 tcg gag tac ctg agc ccg ggt ctg gtg cag ttt gcccgt gcg acg gaa 17892 Ser Glu Tyr Leu Ser Pro Gly Leu Val Gln Phe AlaArg Ala Thr Glu 525 530 535 acc tac ttc tca ctg ggc aac aag ttc agg aacccc acc gtg gcg ccc 17940 Thr Tyr Phe Ser Leu Gly Asn Lys Phe Arg AsnPro Thr Val Ala Pro 540 545 550 555 acc cac gac gtc acc acc gat cgg tcccag cga ctg aca atc cgc ttc 17988 Thr His Asp Val Thr Thr Asp Arg SerGln Arg Leu Thr Ile Arg Phe 560 565 570 gtc ccc gtg gac aag gaa gac accgct tac tcc tac aaa acc cgc ttc 18036 Val Pro Val Asp Lys Glu Asp ThrAla Tyr Ser Tyr Lys Thr Arg Phe 575 580 585 acg ctg gcc gtg ggc gac aaccgg gtg cta gac atg gcc agt acc tac 18084 Thr Leu Ala Val Gly Asp AsnArg Val Leu Asp Met Ala Ser Thr Tyr 590 595 600 ttt gac atc cgc ggc gtgatc gac cgc gga cct agc ttc aag cct tac 18132 Phe Asp Ile Arg Gly ValIle Asp Arg Gly Pro Ser Phe Lys Pro Tyr 605 610 615 tcc ggc acg gct tacaac tca ctg gct ccc aaa ggg gcg ccc aac aac 18180 Ser Gly Thr Ala TyrAsn Ser Leu Ala Pro Lys Gly Ala Pro Asn Asn 620 625 630 635 agc caa tggaac gcc aca gat aac ggg aac aag cca gtg tgt ttt gct 18228 Ser Gln TrpAsn Ala Thr Asp Asn Gly Asn Lys Pro Val Cys Phe Ala 640 645 650 cag gcagct ttt ata ggt caa agc att aca aaa gac gga gtg caa ata 18276 Gln AlaAla Phe Ile Gly Gln Ser Ile Thr Lys Asp Gly Val Gln Ile 655 660 665 cagaac tca gaa aat caa cag gct gct gcc gac aaa act tac caa cca 18324 GlnAsn Ser Glu Asn Gln Gln Ala Ala Ala Asp Lys Thr Tyr Gln Pro 670 675 680gag cct caa att gga gtt tcc acc tgg gat acc aac gtt acc agt aac 18372Glu Pro Gln Ile Gly Val Ser Thr Trp Asp Thr Asn Val Thr Ser Asn 685 690695 gct gcc gga cga gtg tta aaa gcc acc act ccc atg ctg cca tgt tac18420 Ala Ala Gly Arg Val Leu Lys Ala Thr Thr Pro Met Leu Pro Cys Tyr700 705 710 715 ggt tca tat gcc aat ccc act aat cca aac ggg ggt cag gcaaaa aca 18468 Gly Ser Tyr Ala Asn Pro Thr Asn Pro Asn Gly Gly Gln AlaLys Thr 720 725 730 gaa gga gac att tcg cta aac ttt ttc aca aca act gcggca gca gac 18516 Glu Gly Asp Ile Ser Leu Asn Phe Phe Thr Thr Thr AlaAla Ala Asp 735 740 745 aat aat ccc aaa gtg gtt ctt tac agc gaa gat gtaaac ctt caa gcc 18564 Asn Asn Pro Lys Val Val Leu Tyr Ser Glu Asp ValAsn Leu Gln Ala 750 755 760 ccc gat act cac tta gta tat aag cca acg gtggga gaa aac gtt atc 18612 Pro Asp Thr His Leu Val Tyr Lys Pro Thr ValGly Glu Asn Val Ile 765 770 775 gcc gca gaa gcc ctg cta acg cag cag gcgtgt ccc aac aga gca aac 18660 Ala Ala Glu Ala Leu Leu Thr Gln Gln AlaCys Pro Asn Arg Ala Asn 780 785 790 795 tac ata ggt ttc cga gat aac tttatc ggt tta atg tat tat aac agc 18708 Tyr Ile Gly Phe Arg Asp Asn PheIle Gly Leu Met Tyr Tyr Asn Ser 800 805 810 aca ggg aac atg gga gtt ctggca ggt cag gcc tcg cag tta aac gca 18756 Thr Gly Asn Met Gly Val LeuAla Gly Gln Ala Ser Gln Leu Asn Ala 815 820 825 gtt gta gac ctg caa gatcga aac acg gaa ctg tcc tat cag cta atg 18804 Val Val Asp Leu Gln AspArg Asn Thr Glu Leu Ser Tyr Gln Leu Met 830 835 840 cta gat gct ctg ggtgac aga act cga tat ttc tca atg tgg aat cag 18852 Leu Asp Ala Leu GlyAsp Arg Thr Arg Tyr Phe Ser Met Trp Asn Gln 845 850 855 gcc gtg gac agctac gat cca gac gtt agg att atc gag aac cat ggg 18900 Ala Val Asp SerTyr Asp Pro Asp Val Arg Ile Ile Glu Asn His Gly 860 865 870 875 gtg gaagac gag ctg ccc aat tac tgt ttt cca ctc cca ggc atg ggt 18948 Val GluAsp Glu Leu Pro Asn Tyr Cys Phe Pro Leu Pro Gly Met Gly 880 885 890 attttt aac tcc tac aag ggg gta aaa cca caa aat ggc ggt aat ggt 18996 IlePhe Asn Ser Tyr Lys Gly Val Lys Pro Gln Asn Gly Gly Asn Gly 895 900 905aac tgg gaa gca aac ggg gac cta tca aat gcc aat gag atc gct tta 19044Asn Trp Glu Ala Asn Gly Asp Leu Ser Asn Ala Asn Glu Ile Ala Leu 910 915920 gga aac att ttt gcc atg gaa att aac ctc cac gca aac ctg tgg cgc19092 Gly Asn Ile Phe Ala Met Glu Ile Asn Leu His Ala Asn Leu Trp Arg925 930 935 agc ttc ttg tac agc aat gtg gcg ctg tac ctg cca gac agc tataaa 19140 Ser Phe Leu Tyr Ser Asn Val Ala Leu Tyr Leu Pro Asp Ser TyrLys 940 945 950 955 ttc act ccc gct aac atc act ctg ccc gcc aac caa aacacc tac gag 19188 Phe Thr Pro Ala Asn Ile Thr Leu Pro Ala Asn Gln AsnThr Tyr Glu 960 965 970 tat atc aac ggg cgc gtc act tct cca acc ctg gtggac acc ttt gtt 19236 Tyr Ile Asn Gly Arg Val Thr Ser Pro Thr Leu ValAsp Thr Phe Val 975 980 985 aac att gga gcc cga tgg tcg ccg gat ccc atggac aac gtc aac ccc 19284 Asn Ile Gly Ala Arg Trp Ser Pro Asp Pro MetAsp Asn Val Asn Pro 990 995 1000 ttt aac cat cac cgg aac gcg ggc ctc cgttac cgc tcc atg ctg 19329 Phe Asn His His Arg Asn Ala Gly Leu Arg TyrArg Ser Met Leu 1005 1010 1015 ctg gga aat gga cgc gtg gtg cct ttc cacata caa gtg ccg caa 19374 Leu Gly Asn Gly Arg Val Val Pro Phe His IleGln Val Pro Gln 1020 1025 1030 aaa ttt ttc gcg att aag aac ctc ctg cttttg ccc ggc tcc tac 19419 Lys Phe Phe Ala Ile Lys Asn Leu Leu Leu LeuPro Gly Ser Tyr 1035 1040 1045 act tac gag tgg agc ttc aga aaa gac gtgaac atg att ctg cag 19464 Thr Tyr Glu Trp Ser Phe Arg Lys Asp Val AsnMet Ile Leu Gln 1050 1055 1060 agc acc ctg ggc aat gat ctt cga gtg gacggg gcc agc gtc cgc 19509 Ser Thr Leu Gly Asn Asp Leu Arg Val Asp GlyAla Ser Val Arg 1065 1070 1075 att gac agc gtc aac ttg tac gcc aac tttttc ccc atg gcg cac 19554 Ile Asp Ser Val Asn Leu Tyr Ala Asn Phe PhePro Met Ala His 1080 1085 1090 aac acc gct tct acc ttg gaa gcc atg ctgcga aac gac acc aac 19599 Asn Thr Ala Ser Thr Leu Glu Ala Met Leu ArgAsn Asp Thr Asn 1095 1100 1105 gac cag tcg ttt aac gac tac ctc agc gcggcc aac atg ctt tat 19644 Asp Gln Ser Phe Asn Asp Tyr Leu Ser Ala AlaAsn Met Leu Tyr 1110 1115 1120 ccc att ccg gcc aac gcc acc aac gtt cccatt tcc att ccc tcc 19689 Pro Ile Pro Ala Asn Ala Thr Asn Val Pro IleSer Ile Pro Ser 1125 1130 1135 cgc aac tgg gcg gcc ttc cgg gga tgg agcttc acc cgc ctt aaa 19734 Arg Asn Trp Ala Ala Phe Arg Gly Trp Ser PheThr Arg Leu Lys 1140 1145 1150 gcc aag gaa acg cct tcc ttg ggc tcc ggcttt gac ccc tac ttt 19779 Ala Lys Glu Thr Pro Ser Leu Gly Ser Gly PheAsp Pro Tyr Phe 1155 1160 1165 gtg tac tca ggc acc att cct tac ctg gacggc agc ttt tac ctc 19824 Val Tyr Ser Gly Thr Ile Pro Tyr Leu Asp GlySer Phe Tyr Leu 1170 1175 1180 aac cac act ttc aaa cgt ctg tcc atc atgttc gat tct tcc gta 19869 Asn His Thr Phe Lys Arg Leu Ser Ile Met PheAsp Ser Ser Val 1185 1190 1195 agt tgg ccg ggc aac gac cgc ctc ctg acgccg aac gag ttc gaa 19914 Ser Trp Pro Gly Asn Asp Arg Leu Leu Thr ProAsn Glu Phe Glu 1200 1205 1210 att aag cgc att gtg gac ggg gaa ggc tacaac gtg gct caa agt 19959 Ile Lys Arg Ile Val Asp Gly Glu Gly Tyr AsnVal Ala Gln Ser 1215 1220 1225 aac atg acc aaa gac tgg ttt tta att caaatg ctc agc cac tac 20004 Asn Met Thr Lys Asp Trp Phe Leu Ile Gln MetLeu Ser His Tyr 1230 1235 1240 aac atc ggc tac caa ggc ttc tat gtt cccgag ggc tac aag gat 20049 Asn Ile Gly Tyr Gln Gly Phe Tyr Val Pro GluGly Tyr Lys Asp 1245 1250 1255 cgg atg tat tct ttc ttc cga aac ttt cagccc atg agc cgc cag 20094 Arg Met Tyr Ser Phe Phe Arg Asn Phe Gln ProMet Ser Arg Gln 1260 1265 1270 gtg ccg gat ccc acc gct gcc ggc tat caagcc gtt ccc ctg ccc 20139 Val Pro Asp Pro Thr Ala Ala Gly Tyr Gln AlaVal Pro Leu Pro 1275 1280 1285 aga caa cac aac aac tcg ggc ttt gtg gggtac atg ggc ccg acc 20184 Arg Gln His Asn Asn Ser Gly Phe Val Gly TyrMet Gly Pro Thr 1290 1295 1300 atg cgc gaa gga cag cca tac ccg gcc aactac ccc tat ccc ctg 20229 Met Arg Glu Gly Gln Pro Tyr Pro Ala Asn TyrPro Tyr Pro Leu 1305 1310 1315 atc ggc gct acc gcc gtc ccc gcc att acccag aaa aag ttt ttg 20274 Ile Gly Ala Thr Ala Val Pro Ala Ile Thr GlnLys Lys Phe Leu 1320 1325 1330 tgc gac cgc gtc atg tgg cgc ata cct ttttcc agc aac ttt atg 20319 Cys Asp Arg Val Met Trp Arg Ile Pro Phe SerSer Asn Phe Met 1335 1340 1345 tca atg ggg gcc ctg acc gac ctc gga cagaac atg ctt tac gct 20364 Ser Met Gly Ala Leu Thr Asp Leu Gly Gln AsnMet Leu Tyr Ala 1350 1355 1360 aac tcc gcc cat gcc ctg gat atg act tttgag gtg gac ccc atg 20409 Asn Ser Ala His Ala Leu Asp Met Thr Phe GluVal Asp Pro Met 1365 1370 1375 aac gag ccc acg ttg ctg tac atg ctt tttgag gtg ttc gac gtg 20454 Asn Glu Pro Thr Leu Leu Tyr Met Leu Phe GluVal Phe Asp Val 1380 1385 1390 gtc aga gtg cac cag ccg cac cgc ggt attatc gag gcc gtg tac 20499 Val Arg Val His Gln Pro His Arg Gly Ile IleGlu Ala Val Tyr 1395 1400 1405 ctg cgc acc ccc ttc tct gcg ggc aat gccacc aca taa gccgctgaac 20548 Leu Arg Thr Pro Phe Ser Ala Gly Asn Ala ThrThr 1410 1415 1420 tagctggttt ttaccccaga tcccatgggc tccacggaagacgaactgcg ggccattgtg 20608 cgagacctgg gctgcggacc ctacttcctg ggcacctttgacaagcggtt tcccgggttc 20668 gtgtctcctc gcaaactcgc gtgcgcgatc gtgaataccgccggccgaga gaccggagga 20728 gagcattggc tagctctggg ctggaacccc cgctcgtccacgtttttcct gttcgacccc 20788 tttggctttt cagaccaacg cttgaagcag atctatgcatttgaatatga gggtctactc 20848 aagcgaagcg cgctggcctc ctccgccgat cactgtctaaccctggtaaa gagcactcag 20908 acggttcagg gccctcacag cgccgcctgt ggccttttttgttgcatgtt tttgcacgcc 20968 tttgtgaact ggccggacac ccccatggaa aacaaccccaccatggacct cctgactggc 21028 gttcccaact ccatgctcca aagccccagc gtgcagaccaccctcctcca aaaccagaaa 21088 aatctgtacg cctttctgca caagcactct ccctactttcgccgccatcg ggaacaaata 21148 gaaaatgcaa ccgcgtttaa caaaactctg taacgtttaataaatgaact ttttattgaa 21208 ctggaaaacg ggtttgtgat ttttaaaaat caaaggggttgagctggaca tccatgtggg 21268 aggccggaag ggtggtgttc ttgtactggt acttgggcagccacttaaac tctggaatca 21328 caaacttggg cagcggtatt tctgggaagt tgtcgtgccacagctggcgg gtcagctgaa 21388 gtgcctgcag aacatcgggg gcggagatct tgaagtcgcagtttatctgg ttcacggcac 21448 gcgcgttgcg gtacatggga ttggcacact gaaacaccagcaggctggga ttcttgatgc 21508 tagccagggc cacggcgtcg gtcacgtcac cggtgtcttctatgttggac agcgaaaaag 21568 gcgtgacttt gcaaagctgg cgtcccgcgc gaggcacgcaatctcccagg tagttgcact 21628 cacagcggat gggcagaaga agatgcttgt ggccgcgggtcatgtaggga taggccgctg 21688 ccataaaagc ttcgatctgc ctgaaagcct gcttggccttgtgcccttcg gtataaaaaa 21748 caccgcagga cttgttggaa aaggtattac tggcgcaagcggcatcgtga aagcaagcgc 21808 gtgcgtcttc gtttcgtaac tgcaccacgc tgcggccccaccggttctga atcaccttgg 21868 ccctgccggg gttttccttg agagcgcgct ggccggcttcgctgcccaca tccatttcca 21928 cgacatgctc cttgttaatc atggccagac cgtggaggcagcgcagctcc tcgtcatcgt 21988 cggtgcagtg atgctcccac acgacgcagc cagtgggctcccacttgggc ttggaggcct 22048 cggcaatgcc agaatacagg agaacgtagt ggtgcagaaaacgtcccatc atggtgccaa 22108 aggttttctg gctgctgaag gtcatcgggc agtacctccagtcctcgtta agccaagtgt 22168 tgcagatctt cctgaagacc gtgtactgat cgggcataaagtggaactca ttgcgctcgg 22228 tcttgtcgat cttatacttt tccatcagac tatgcataatctccatgccc ttttcccagg 22288 cgcaaacaat cttggtgcta cacgggttag gtatggccaaagtggttggc ctctgaggcg 22348 gcgcttgttc ttcctcttga gccctctccc gactgacgggggttgaaaga gggtgcccct 22408 tggggaacgg cttgaacacg gtctggcccg aggcgtcccgaagaatctgc atcgggggat 22468 tgctggccgt catggcgatg atctgacccc ggggctcctccacttcgtcc tcctcgggac 22528 tttcctcgtg cttttcgggg gacggtacgg gagtagggggaagagcgcgg cgcgccttct 22588 tcttgggcgg cagttccgga gcctgctctt gacgactggccattgtcttc tcctaggcaa 22648 gaaaaacaag atggaagact ctttctcctc ctcctcgtcaacgtcagaaa gcgagtcttc 22708 caccttaagc gccgagaact cccagcgcat agaatccgatgtgggctacg agactccccc 22768 cgcgaacttt tcgccgcccc ccataaacac taacgggtggacggactacc tggccctagg 22828 agacgtactg ctgaagcaca tcaggcggca gagcgttatcgtgcaagatg ctctcaccga 22888 gcgactcgcg gttccgctgg aagtggcgga acttagcgccgcctacgagc gaaccctctt 22948 ctccccaaag actcccccca agaggcaggc taacggcacctgcgagccta accctcgact 23008 caacttctac cctgcctttg ccgtgccaga ggtactggctacgtaccaca tttttttcca 23068 aaaccacaaa atccctctct cgtgccgcgc caaccgcaccaaagccgatc gcgtgctgcg 23128 actggaggaa ggggctcgca tacctgagat tgcgtgtctggaggaagtcc caaaaatctt 23188 tgaaggtctg ggccgcgacg aaaagcgagc agcaaacgctctggaagaga acgcagagag 23248 tcacaacagc gccttggtag aactcgaggg cgacaacgccagactggccg tcctcaaacg 23308 gtccatagaa gtcacgcact tcgcctaccc cgccgttaacctccctccaa aagttatgac 23368 agcggtcatg gactcgctgc tcataaagcg cgctcagcccttagacccag agcacgaaaa 23428 caacagtgac gaaggaaaac cggtggtttc tgatgaggagttgagcaagt ggctgtcctc 23488 caacgacccc gccacgttgg aggaacgaag aaaaaccatgatggccgtgg tgctagttac 23548 cgtgcaatta gaatgtctgc agaggttctt ttcccacccagagaccctga gaaaagtgga 23608 ggaaacgctg cactacacat ttaggcacgg ctacgtgaagcaagcctgca agatttccaa 23668 cgtagaactt agcaacctca tctcctacct ggggatcttgcacgaaaacc gcctcggaca 23728 aaacgtgctg cacagcacac tgaaaggaga agcccgccgagactatgtgc gagactgcgt 23788 gttcctagcg ctagtgtaca cctggcagag cggaatgggagtctggcagc agtgcctgga 23848 ggacgaaaac ctcaaagagc ttgaaaagct gctggtgcgctccagaaggg cactgtggac 23908 cagttttgac gagcgcaccg ccgcgcgaga cctagctgatattatttttc ctcccaagct 23968 ggtgcagact ctccgggaag gactgccaga ttttatgagtcaaagcatct tgcaaaactt 24028 ccgctctttc atcttggaac gctcgggaat cttgcccgccactagctgcg ccctacccac 24088 agattttgtg cctctccact accgcgaatg cccaccgccgctgtggccgt acacttactt 24148 gcttaaactg gccaactttc taatgttcca ctctgacctggcagaagacg ttagcggcga 24208 ggggctgcta gaatgccact gccgctgcaa cctgtgcaccccccaccgct ctctagtatg 24268 caacactccc ctgctcaatg agacccagat catcggtacctttgaaatcc agggaccctc 24328 cgacgcggaa aacggcaagc aggggtctgg gctaaaactcacagccggac tgtggacctc 24388 cgcctacttg cgcaaatttg taccagaaga ctatcacgcccaccaaatta aattttacga 24448 aaaccaatca aaaccaccca aaagcgagtt aacggcttgcgtcattacgc agagcagcat 24508 agttgggcag ttgcaagcca ttaacaaagc gcggcaagagtttctcctaa aaaaaggaaa 24568 aggggtctac ttggaccccc agaccggcga ggaactcaacggaccctcct cagtcgcagg 24628 ttgtgtgccc catgccgccc aaaaagaaca cctcgcagtggaacatgcca gagacggagg 24688 aagaggagtg gagcagtgtg agcaacagcg aaacggaggaagagccgtgg cccgaggggt 24748 gcaacgggga agaggacacg gagggacggc gaagtcttcgccgaagaact ctcgccgctg 24808 cccccgaagt cccagccggc cgcctcggcc caagatcccgcacacacccg tagatgggat 24868 agcaagacca aaaagccggg taagagaaac gctcgcccccgccagggcta ccgctcgtgg 24928 agaaagcaca aaaactgcat cttatcgtgc ttgctccagtgcggcggaga cgtttcgttc 24988 acccgtagat acttgctttt taacaaaggg gtggccgtcccccgtaacgt cctccactac 25048 taccgtcact cttacagctc cgaagcggac ggctaagaaaacgcagcagt tgccggcggg 25108 aggactgcgt ctcagcgccc gagaaccccc agccaccagggagctccgaa accgcatatt 25168 tcccaccctc tacgctatct ttcagcaaag ccgggggcagcagcaagaac tgaaaataaa 25228 aaaccgcacg ctgaggtcgc ttacccgaag ctgcctctatcacaagagcg aagagcagct 25288 gcagcgaacc ctggaggacg cagaagcgct gttccagaagtactgcgcga ccaccctaaa 25348 taactaaaaa agcccgcgcg cgggacttca aaccgtctgacgtcaccagc cgcgcgccaa 25408 aatgagcaaa gagattccca cgccttacat gtggagttaccagccgcaga tgggattagc 25468 cgccggcgcc gcccaggatt actccacgaa aatgaactggctcagcgccg ggccccacat 25528 gatttcccgc gtaaacgaca ttcgcgccca ccgcaatcagctattgttag aacaggctgc 25588 tctgaccgcc acgccccgta ataacctgaa ccctcccagctggccagctg ccctggtgta 25648 ccaggaaacg cctccaccca ccagcgtact tttgccccgtgacgcccagg cggaagtcca 25708 gatgactaac gcgggcgcgc aattagcggg cggatcccggtttcggtaca gagttcacgg 25768 cgccgcaccc tatagcccag gtataaagag gctgatcattcgaggcagag gtgtccagct 25828 caacgacgag acagtgagct cttcgcttgg tctacgaccagacggagtgt tccagctcgc 25888 gggctcgggc cgctcttcgt tcacgcctcg ccaggcatacctgactctgc agagctctgc 25948 ctctcagcct cgctcgggag gaatcggacc ccttcagtttgtggaggagt ttgtgccctc 26008 ggtctacttt cagcctttct ccggatcgcc cggccagtacccggacgagt tcatccccaa 26068 cttcgacgcg gtgagtgact ctgtggacgg ttatgactgatgtcgagccc gcttcagtgc 26128 tagtggaaca agcgcggctc aatcacctgg ttcgttgccgccgccgctgc tgcgtggctc 26188 gcgacttgag cttagctctc aagtttgtaa aaaacccgtccgaaaccggg agcgctgtgc 26248 acgggttgga gctagtgggt cctgagaagg ccaccatccacgttctcaga aactttgtgg 26308 aaaaacccat tttggttaaa cgagatcagg ggccttttgtaatcagctta ctctgcacct 26368 gtaaccatgt tgaccttcac gactatttta tggatcatttgtgcgctgaa ttcaataagt 26428 aaagcgaatt cttaccaaga ttatgatgtc catgactgttcctcgccact atacgatgtt 26488 gtgccagtaa actctcttgt cgacatctat ctgaactgttccttttggtc cgcacagctt 26548 acttggtact acggtgacac cgtcctttct ggctcactgggcagctcaca cggaataaca 26608 cttcacctct tttcgccgtt tcgatacgga aactacagctgtcgtgccgg tacctgcctc 26668 cacgttttca atcttcagcc ctgtccaccg accaaacttgtatttgtcga ctctaagcac 26728 ttacagctca actgcagcat tctaggcccc agtatcttgtggacatacaa taaaatcagg 26788 ttggtggaat ttgtctacta cccacccagc gcccgcggttttggggaaat tcctttccag 26848 atctactaca actatcttgc cacacattat gcaagtcaacagcaactaaa cttgcaagca 26908 cccttcacgc caggagagta ctcctgtcac gtaggctcctgcacagaaac ttttattctc 26968 ttcaacagat cttctgccat tgaacgcttc actactaactactttagaaa ccaagttgtg 27028 cttttcactg acgaaacccc taacgtcacc ctggactgtgcatgtttttc tcatgacacc 27088 gtaacttgga ctcttaacaa tactctctgg ctcgcgttcgataaccaaag cttgattgtt 27148 aaaaattttg atttaacctt tactaaaccc tctcctcgcgaaatagttat ctttgctcct 27208 tttaatccaa aaactacctt agcctgtcag gttttgtttaagccttgcca aacaaacttt 27268 aagtttgttt atttgcctcc gcaatctgtc aaactcatagaaaaatacaa caaagcgccc 27328 gtcttggctc ctaaaacctt ctaccactgg ctaacctacacggggctgtt tgcactaatt 27388 gtttttttcc taattaacat ttttatatgt ttcttgccttcctccttctt ttcgcgaaca 27448 ccgttgccgc agaaagacct ctccttatta ctgtagcgcttgctatacaa aaccaagagt 27508 ggtcaaccgt gctctcaatc tattttcaat ttttcattttgtccttaata ctttctctta 27568 ttgtcgttaa caatgatctg gagcattggt ctcgcctttttttggctgct tagtgcaaaa 27628 gccactattt ttcacaggta tgtggaagaa ggaactagcaccctctttac gatacctgaa 27688 acaattaagg cggctgatga agtttcttgg tacaaaggctcgctctcaga cggcaaccac 27748 tcattctcag gacagaccct ttgcatccaa gaaacttattttaaatcaga actacaatac 27808 agctgcataa aaaacttttt ccatctctac aacatctcaaaaccctatga gggtatttac 27868 aatgccaagg tttcagacaa ctccagcaca cggaacttttactttaatct gacagttatt 27928 aaagcaattt ccattcctat ctgtgagttt agctcccagtttctttctga aacctactgt 27988 ttaattacta taaactgcac taaaaatcgc cttcacaccaccataatcta caatcacaca 28048 caatcacctt gggttttaaa cctaaaattt tctccacacatgccttcgca atttctcacg 28108 caagttaccg tctctaacat aagcaagcag tttggcttttactatccttt ccacgaactg 28168 tgcgaaataa ttgaagccga atatgaacca gactactttacttacattgc cattggtgta 28228 atcgttgttt gcctttgctt tgttattggg gggtgtgtttatttgtacat tcagagaaaa 28288 atattgctct cgctgtgctc ctgcggttac aaagcagaagaaagaattaa aatctctaca 28348 ctttattaat gttttccaga aatggcaaaa ctaacgctcctacttttgct tctcacgccg 28408 gtgacgcttt ttaccatcac tttttctgcc gccgccacactcgaacctca atgtttgcca 28468 ccggttgaag tctactttgt ctacgtgttg ctgtgctgcgttagcgtttg cagtataaca 28528 tgttttacct ttgtttttct tcagtgcatt gactacttctgggtcagact ctactaccgc 28588 agacacgcgc ctcagtatca aaatcaacaa attgccagactactcggtct gccatgattg 28648 tcttgtattt taccctgatt ttttttcacc ttacttgcgcttgtgatttt cacttcactc 28708 aattttggaa aacgcaatgc ttcgacccgc gcctctccaacgactggatg atggctcttg 28768 caattgccac gcttggggcg tttggacttt ttagtggttttgctttgcat tacaaattta 28828 agactccatg gacacatggc tttctttcag attttccagttacacctact ccgccgcctc 28888 ccccggccat cgacgtgcct caggttccct caccttctccatctgtctgc agctactttc 28948 atctgtaatg gccgacctag aatttgacgg agtgcaatctgagcaaaggg ctatacactt 29008 ccaacgccag tcggaccgcg aacgcaaaaa cagagagctgcaaaccatac aaaacaccca 29068 ccaatgtaaa cgcgggatat tttgtattgt aaaacaagctaagctccact acgagcttct 29128 atctggcaac gaccacgagc tccaatacgt ggtcgatcagcagcgtcaaa cctgtgtatt 29188 cttaattgga gtttccccca ttaaagttac tcaaaccaagggtgaaacca agggaaccat 29248 aaggtgctca tgtcacctgt cagaatgcct ttacactctagttaaaaccc tatgtggctt 29308 acatgattct atccccttta attaaataaa cttactttaaatctgcaatc acttcttcgt 29368 ccttgttttt gtcgccatcc agcagcacca ccttcccctcttcccaactt tcatagcata 29428 ttttccgaaa agaggcgtac tttcgccaca ccttaaagggaacgtttact tcgctttcaa 29488 gctctcccac gattttcatt gcagat atg aaa cgc gccaaa gtg gaa gaa gga 29541 Met Lys Arg Ala Lys Val Glu Glu Gly 1425 tttaac ccc gtt tat ccc tat gga tat tct act ccg act gac gtg 29586 Phe AsnPro Val Tyr Pro Tyr Gly Tyr Ser Thr Pro Thr Asp Val 1430 1435 1440 gctcct ccc ttt gta gcc tct gac ggt ctt caa gaa aac cca cct 29631 Ala ProPro Phe Val Ala Ser Asp Gly Leu Gln Glu Asn Pro Pro 1445 1450 1455 ggggtc ttg tcc cta aaa ata tcc aaa cct tta act ttt aat gcc 29676 Gly ValLeu Ser Leu Lys Ile Ser Lys Pro Leu Thr Phe Asn Ala 1460 1465 1470 tccaag gct cta agc ctg gct att ggt cca gga tta aaa att caa 29721 Ser LysAla Leu Ser Leu Ala Ile Gly Pro Gly Leu Lys Ile Gln 1475 1480 1485 gatggt aaa cta gtg ggg gag gga caa gca att ctt gca aac ctg 29766 Asp GlyLys Leu Val Gly Glu Gly Gln Ala Ile Leu Ala Asn Leu 1490 1495 1500 ccgctt caa atc acc aac aac aca att tca cta cgt ttt ggg aac 29811 Pro LeuGln Ile Thr Asn Asn Thr Ile Ser Leu Arg Phe Gly Asn 1505 1510 1515 acactt gcc ttg aat gac aat aat gaa ctc caa acc aca cta aaa 29856 Thr LeuAla Leu Asn Asp Asn Asn Glu Leu Gln Thr Thr Leu Lys 1520 1525 1530 tcttca tcg ccc ctt aaa atc aca gac cag act ctg tcc ctt aac 29901 Ser SerSer Pro Leu Lys Ile Thr Asp Gln Thr Leu Ser Leu Asn 1535 1540 1545 ataggg gac agc ctt gca att aaa gat gac aaa cta gaa agc gct 29946 Ile GlyAsp Ser Leu Ala Ile Lys Asp Asp Lys Leu Glu Ser Ala 1550 1555 1560 cttcaa gcg acc ctc cca ctc tcc att agc aac aac acc atc agc 29991 Leu GlnAla Thr Leu Pro Leu Ser Ile Ser Asn Asn Thr Ile Ser 1565 1570 1575 ctcaac gtg ggc acc gga ctc acc ata aat gga aac gtt tta caa 30036 Leu AsnVal Gly Thr Gly Leu Thr Ile Asn Gly Asn Val Leu Gln 1580 1585 1590 gctgtt ccc tta aat gct cta agt ccc cta act att tcc aac aat 30081 Ala ValPro Leu Asn Ala Leu Ser Pro Leu Thr Ile Ser Asn Asn 1595 1600 1605 aacatc agc ctg cgc tat ggc agt tcc ctg acg gtg ctt aac aat 30126 Asn IleSer Leu Arg Tyr Gly Ser Ser Leu Thr Val Leu Asn Asn 1610 1615 1620 gaactg caa agc aac ctc aca gtt cac tcc cct tta aaa ctc aac 30171 Glu LeuGln Ser Asn Leu Thr Val His Ser Pro Leu Lys Leu Asn 1625 1630 1635 tccaac aac tca att tct ctc aac act cta tct ccg ttt aga atc 30216 Ser AsnAsn Ser Ile Ser Leu Asn Thr Leu Ser Pro Phe Arg Ile 1640 1645 1650 gagaat ggt ttc ctc acg ctc tat ttg gga aca aaa tct ggc ttg 30261 Glu AsnGly Phe Leu Thr Leu Tyr Leu Gly Thr Lys Ser Gly Leu 1655 1660 1665 ctagtt caa aac agt ggc tta aaa gtt caa gcg ggc tac ggc ctg 30306 Leu ValGln Asn Ser Gly Leu Lys Val Gln Ala Gly Tyr Gly Leu 1670 1675 1680 caagta aca gac acc aat gct ctc aca tta aga tat ctc gct cca 30351 Gln ValThr Asp Thr Asn Ala Leu Thr Leu Arg Tyr Leu Ala Pro 1685 1690 1695 ctgacc att cca gac tcg ggc tca gaa caa ggc att ctt aaa gta 30396 Leu ThrIle Pro Asp Ser Gly Ser Glu Gln Gly Ile Leu Lys Val 1700 1705 1710 aacact gga cag ggc cta agt gtg aac caa gct gga gcg ctt gaa 30441 Asn ThrGly Gln Gly Leu Ser Val Asn Gln Ala Gly Ala Leu Glu 1715 1720 1725 acatcc cta gga ggt gga tta aaa tat gct gat aac aaa ata acc 30486 Thr SerLeu Gly Gly Gly Leu Lys Tyr Ala Asp Asn Lys Ile Thr 1730 1735 1740 tttgat aca gga aac gga ctg aca tta tct gaa aat aaa ctt gca 30531 Phe AspThr Gly Asn Gly Leu Thr Leu Ser Glu Asn Lys Leu Ala 1745 1750 1755 gtagct gca ggt agt ggt cta act ttt aga gat ggt gcc ttg gta 30576 Val AlaAla Gly Ser Gly Leu Thr Phe Arg Asp Gly Ala Leu Val 1760 1765 1770 gccacg gga acc gca ttt acg caa aca ctg tgg act acg gct gat 30621 Ala ThrGly Thr Ala Phe Thr Gln Thr Leu Trp Thr Thr Ala Asp 1775 1780 1785 ccgtct ccc aac tgc aca att ata cag gac cgc gac aca aaa ttt 30666 Pro SerPro Asn Cys Thr Ile Ile Gln Asp Arg Asp Thr Lys Phe 1790 1795 1800 actttg gcg ctt acc att agt ggg agc caa gtg ctg ggg acg gtt 30711 Thr LeuAla Leu Thr Ile Ser Gly Ser Gln Val Leu Gly Thr Val 1805 1810 1815 tccatt att gga gta aaa ggc ccc ctt tca agt agc ata ccg tca 30756 Ser IleIle Gly Val Lys Gly Pro Leu Ser Ser Ser Ile Pro Ser 1820 1825 1830 gctacc gtt aca gta caa ctt aac ttt gat tcc aac gga gcc cta 30801 Ala ThrVal Thr Val Gln Leu Asn Phe Asp Ser Asn Gly Ala Leu 1835 1840 1845 ttgagc tcc tct tca ctt aaa ggt tac tgg ggg tat cgc caa ggt 30846 Leu SerSer Ser Ser Leu Lys Gly Tyr Trp Gly Tyr Arg Gln Gly 1850 1855 1860 ccctca att gac cct tac ccc ata att aat gcc tta aac ttt atg 30891 Pro SerIle Asp Pro Tyr Pro Ile Ile Asn Ala Leu Asn Phe Met 1865 1870 1875 ccaaac tca ctg gct tat ccc ccg gga caa gaa atc caa gca aaa 30936 Pro AsnSer Leu Ala Tyr Pro Pro Gly Gln Glu Ile Gln Ala Lys 1880 1885 1890 tgtaac atg tac gtt tct act ttt tta cga gga aat cca caa aga 30981 Cys AsnMet Tyr Val Ser Thr Phe Leu Arg Gly Asn Pro Gln Arg 1895 1900 1905 ccaata gtt tta aac atc act ttt aat aat caa acc agc ggg ttt 31026 Pro IleVal Leu Asn Ile Thr Phe Asn Asn Gln Thr Ser Gly Phe 1910 1915 1920 tccatt aga ttt aca tgg aca aat tta acc aca gga gaa gca ttt 31071 Ser IleArg Phe Thr Trp Thr Asn Leu Thr Thr Gly Glu Ala Phe 1925 1930 1935 gcaatg ccc cca tgc act ttt tcc tac att gct gaa caa caa taa 31116 Ala MetPro Pro Cys Thr Phe Ser Tyr Ile Ala Glu Gln Gln 1940 1945 1950actatgtaac cctcaccgtt aacccgcctc cgcccttcca ttttatttta taaaccaccc 31176gatccacctt ttcagcagta aacaattgca tgtcagtagg ggcagtaaaa cttttgggag 31236ttaaaatcca cacaggttct tcacaagcta agcgaaaatc agttacactt ataaaaccat 31296cgctaacatc ggacaaagac aagcatgagt ccaaagcttc cggttctgga tcagattttt 31356gttcattaac agcgggagaa acagcttctg gaggattttc catctccatc tccttcatca 31416gttccaccat gtccaccgtg gtcatctggg acgagaacga cagttgtcat acacctcata 31476agtcaccggt cgatgacgaa cgtacagatc tcgaagaatg tcctgtcgcc gcctttcggc 31536agcactgggc cgaaggcgaa agcgcccatg tttaacaatg gccagcaccg cccgcttcat 31596caggcgccta gttcttttag cgcaacagcg catgcgcagc tcgctaagac tggcgcaaga 31656aacacagcac agaaccacca gattgttcat gatcccataa gcgtgctgac accagcccat 31716actaacaaat tgtttcacta ttctagcatg aatgtcatat ctgatgttca agtaaattaa 31776atggcgcccc cttatgtaaa cacttcccac gtacaacacc tcctttggca tctgataatt 31836aaccacctcc cgataccaaa tacatctctg attaatagtc gccccgtaca ctacccgatt 31896aaaccaagtt gccaacataa tcccccctgc catacactgc aaagaacctg gacggctaca 31956atgacagtgc aaagtccaca cctcgttgcc atggataact gaggaacgcc ttaagtcaat 32016agtggcacaa ctaatacaaa catgtaaata gtgtttcaac aagtgccact cgtatgaggt 32076gagtatcatg tcccagggaa cgggccactc cataaacact gcaaaaccaa cacatcctac 32136catcccccgc acggcactca catcgtgcat ggtgttcata tcacagtccg gaagctgagg 32196acaaggaaaa gtctcgggag cattttcata gggcggtagt gggtactcct tgtaggggtt 32256cagtcggcac cggtatctcc tcaccttctg ggccataaca cacaagttga gatctgattt 32316caaggtactt tctgaatgaa aaccaagtgc tttcccaaca atgtatccga tgtcttcggt 32376ccccgcgtcg gtagcgctcc ttgcagtaca cacggaacaa ccactcacgc aggcccagaa 32436gacagttttc cgcggacggt gacaagttaa tccccctcag tctcagagcc aatatagttt 32496cttccacagt agcataggcc aaacccaacc aggaaacaca agctggcacg tcccgttcaa 32556cgggaggaca aggaagcaga ggcagaggca taggcaaagc aacagaattt ttattccaac 32616tggtcacgta gcacttcaaa caccaggtca cgtaaatggc agcgatcttg ggtttcctga 32676tggaacataa cagcaagatc aaacatgaga cgattctcaa ggtgattaac cacagctgga 32736attaaatcct ccacgcgcac atttagaaac accagcaata caaaagcccg gttttctccg 32796ggatctatca tagcagcaca gtcatcaatt agtcccaagt aattttcccg tttccaatct 32856gttataattt gcagaataat gccctgtaaa tccaagccgg ccatggcgaa aagctcagat 32916aatgcacttt ccacgtgcat tcgtaaacac accctcatct tgtcaatcca aaaagtcttc 32976ttcttgagaa acctgtagta aattaagaat cgccaggtta ggctcgatgc ctacatcccg 33036gagcttcatt ctcagcatgc actgcaaatg atccagcaga tcagaacagc aattagcagc 33096cagctcatcc ccggtttcca gttccggagt tcccacggca attatcactc gaaacgtggg 33156acaaatcgaa ataacatgag ctcccacgtg agcaaaagcc gtagggccag tgcaataatc 33216acagaaccag cggaaaaaag attgcagctc atgtttcaaa aagctctgca gatcaaaatt 33276cagctcatgc aaataacaca gtaaagtttg cggtatagta accgaaaacc acacgggtcg 33336acgttcaaac atctcggctt acctaaaaaa gaagcacatt tttaaaccac agtcgcttcc 33396tgaacaggag gaaatatggt gcggcgtaaa accagacgcg ccaccggatc tccggcagag 33456ccctgataat acagccagct gtggttaaac agcaaaacct ttaattcggc aacggttgag 33516gtctccacat aatcagcgcc cacaaaaatc ccatctcgaa cttgctcgcg tagggagcta 33576aaatggccag tatagcccca tggcacccga acgctaatct gcaagtatat gagagccacc 33636ccattcggcg ggatcacaaa atcagtcgga gaaaacaacg tatacacccc ggactgcaaa 33696agctgttcag gcaaacgccc ctgcggtccc tctcggtaca ccagcaaagc ctcgggtaaa 33756gcagccatgc caagcgctta ccgtgccaag agcgactcag acgaaaaagt gtactgaggc 33816gctcagagca gcggctatat actctacctg tgacgtcaag aaccgaaagt caaaagttca 33876cccggcgcgc ccgaaaaaac ccgcgaaaat ccacccaaaa agcccgcgaa aaacacttcc 33936gtataaaatt tccgggttac cggcgcgtca ccgccgcgcg acacgcccgc cccgccccgc 33996gctcctcccc gaaacccgcc gcgcccactt ccgcgttccc aagacaaagg tcgcgtaact 34056ccgcccacct catttgcatg ttaactcggt cgccatcttg cggtgttata ttgatgatg 3411535 503 PRT simian adenovirus SV-39 35 Met Arg Arg Ala Val Ala Val ProSer Ala Ala Met Ala Leu Gly Pro 1 5 10 15 Pro Pro Ser Tyr Glu Ser ValMet Ala Ala Ala Thr Leu Gln Ala Pro 20 25 30 Leu Glu Asn Pro Tyr Val ProPro Arg Tyr Leu Glu Pro Thr Gly Gly 35 40 45 Arg Asn Ser Ile Arg Tyr SerGlu Leu Thr Pro Leu Tyr Asp Thr Thr 50 55 60 Arg Leu Tyr Leu Val Asp AsnLys Ser Ala Asp Ile Ala Thr Leu Asn 65 70 75 80 Tyr Gln Asn Asp His SerAsn Phe Leu Thr Ser Val Val Gln Asn Ser 85 90 95 Asp Tyr Thr Pro Ala GluAla Ser Thr Gln Thr Ile Asn Leu Asp Asp 100 105 110 Arg Ser Arg Trp GlyGly Asp Leu Lys Thr Ile Leu His Thr Asn Met 115 120 125 Pro Asn Val AsnGlu Phe Met Phe Thr Asn Ser Phe Arg Ala Lys Leu 130 135 140 Met Val AlaHis Glu Ala Asp Lys Asp Pro Val Tyr Glu Trp Val Gln 145 150 155 160 LeuThr Leu Pro Glu Gly Asn Phe Ser Glu Ile Met Thr Ile Asp Leu 165 170 175Met Asn Asn Ala Ile Ile Asp His Tyr Leu Ala Val Ala Arg Gln Gln 180 185190 Gly Val Lys Glu Ser Glu Ile Gly Val Lys Phe Asp Thr Arg Asn Phe 195200 205 Arg Leu Gly Trp Asp Pro Glu Thr Gly Leu Val Met Pro Gly Val Tyr210 215 220 Thr Asn Glu Ala Phe His Pro Asp Val Val Leu Leu Pro Gly CysGly 225 230 235 240 Val Asp Phe Thr Tyr Ser Arg Leu Asn Asn Leu Leu GlyIle Arg Lys 245 250 255 Arg Met Pro Phe Gln Glu Gly Phe Gln Ile Leu TyrGlu Asp Leu Glu 260 265 270 Gly Gly Asn Ile Pro Ala Leu Leu Asp Val ProAla Tyr Glu Glu Ser 275 280 285 Ile Ala Asn Ala Arg Glu Ala Ala Ile ArgGly Asp Asn Phe Ala Ala 290 295 300 Gln Pro Gln Ala Ala Pro Thr Ile LysPro Val Leu Glu Asp Ser Lys 305 310 315 320 Gly Arg Ser Tyr Asn Val IleAla Asn Thr Asn Asn Thr Ala Tyr Arg 325 330 335 Ser Trp Tyr Leu Ala TyrAsn Tyr Gly Asp Pro Glu Lys Gly Val Arg 340 345 350 Ala Trp Thr Leu LeuThr Thr Pro Asp Val Thr Cys Gly Ser Glu Gln 355 360 365 Val Tyr Trp SerLeu Pro Asp Met Tyr Val Asp Pro Val Thr Phe Arg 370 375 380 Ser Thr GlnGln Val Ser Asn Tyr Pro Val Val Gly Ala Glu Leu Met 385 390 395 400 ProIle His Ser Lys Ser Phe Tyr Asn Glu Gln Ala Val Tyr Ser Gln 405 410 415Leu Ile Arg Gln Thr Thr Ala Leu Thr His Val Phe Asn Arg Phe Pro 420 425430 Glu Asn Gln Ile Leu Val Arg Pro Pro Ala Pro Thr Ile Thr Thr Val 435440 445 Ser Glu Asn Val Pro Ala Leu Thr Asp His Gly Thr Leu Pro Leu Gln450 455 460 Asn Ser Ile Arg Gly Val Gln Arg Val Thr Ile Thr Asp Ala ArgArg 465 470 475 480 Arg Thr Cys Pro Tyr Val Tyr Lys Ala Leu Gly Ile ValAla Pro Arg 485 490 495 Val Leu Ser Ser Arg Thr Phe 500 36 917 PRTsimian adenovirus SV-39 36 Met Ala Thr Pro Ser Met Met Pro Gln Trp SerTyr Met His Ile Ala 1 5 10 15 Gly Gln Asp Ala Ser Glu Tyr Leu Ser ProGly Leu Val Gln Phe Ala 20 25 30 Arg Ala Thr Glu Thr Tyr Phe Ser Leu GlyAsn Lys Phe Arg Asn Pro 35 40 45 Thr Val Ala Pro Thr His Asp Val Thr ThrAsp Arg Ser Gln Arg Leu 50 55 60 Thr Ile Arg Phe Val Pro Val Asp Lys GluAsp Thr Ala Tyr Ser Tyr 65 70 75 80 Lys Thr Arg Phe Thr Leu Ala Val GlyAsp Asn Arg Val Leu Asp Met 85 90 95 Ala Ser Thr Tyr Phe Asp Ile Arg GlyVal Ile Asp Arg Gly Pro Ser 100 105 110 Phe Lys Pro Tyr Ser Gly Thr AlaTyr Asn Ser Leu Ala Pro Lys Gly 115 120 125 Ala Pro Asn Asn Ser Gln TrpAsn Ala Thr Asp Asn Gly Asn Lys Pro 130 135 140 Val Cys Phe Ala Gln AlaAla Phe Ile Gly Gln Ser Ile Thr Lys Asp 145 150 155 160 Gly Val Gln IleGln Asn Ser Glu Asn Gln Gln Ala Ala Ala Asp Lys 165 170 175 Thr Tyr GlnPro Glu Pro Gln Ile Gly Val Ser Thr Trp Asp Thr Asn 180 185 190 Val ThrSer Asn Ala Ala Gly Arg Val Leu Lys Ala Thr Thr Pro Met 195 200 205 LeuPro Cys Tyr Gly Ser Tyr Ala Asn Pro Thr Asn Pro Asn Gly Gly 210 215 220Gln Ala Lys Thr Glu Gly Asp Ile Ser Leu Asn Phe Phe Thr Thr Thr 225 230235 240 Ala Ala Ala Asp Asn Asn Pro Lys Val Val Leu Tyr Ser Glu Asp Val245 250 255 Asn Leu Gln Ala Pro Asp Thr His Leu Val Tyr Lys Pro Thr ValGly 260 265 270 Glu Asn Val Ile Ala Ala Glu Ala Leu Leu Thr Gln Gln AlaCys Pro 275 280 285 Asn Arg Ala Asn Tyr Ile Gly Phe Arg Asp Asn Phe IleGly Leu Met 290 295 300 Tyr Tyr Asn Ser Thr Gly Asn Met Gly Val Leu AlaGly Gln Ala Ser 305 310 315 320 Gln Leu Asn Ala Val Val Asp Leu Gln AspArg Asn Thr Glu Leu Ser 325 330 335 Tyr Gln Leu Met Leu Asp Ala Leu GlyAsp Arg Thr Arg Tyr Phe Ser 340 345 350 Met Trp Asn Gln Ala Val Asp SerTyr Asp Pro Asp Val Arg Ile Ile 355 360 365 Glu Asn His Gly Val Glu AspGlu Leu Pro Asn Tyr Cys Phe Pro Leu 370 375 380 Pro Gly Met Gly Ile PheAsn Ser Tyr Lys Gly Val Lys Pro Gln Asn 385 390 395 400 Gly Gly Asn GlyAsn Trp Glu Ala Asn Gly Asp Leu Ser Asn Ala Asn 405 410 415 Glu Ile AlaLeu Gly Asn Ile Phe Ala Met Glu Ile Asn Leu His Ala 420 425 430 Asn LeuTrp Arg Ser Phe Leu Tyr Ser Asn Val Ala Leu Tyr Leu Pro 435 440 445 AspSer Tyr Lys Phe Thr Pro Ala Asn Ile Thr Leu Pro Ala Asn Gln 450 455 460Asn Thr Tyr Glu Tyr Ile Asn Gly Arg Val Thr Ser Pro Thr Leu Val 465 470475 480 Asp Thr Phe Val Asn Ile Gly Ala Arg Trp Ser Pro Asp Pro Met Asp485 490 495 Asn Val Asn Pro Phe Asn His His Arg Asn Ala Gly Leu Arg TyrArg 500 505 510 Ser Met Leu Leu Gly Asn Gly Arg Val Val Pro Phe His IleGln Val 515 520 525 Pro Gln Lys Phe Phe Ala Ile Lys Asn Leu Leu Leu LeuPro Gly Ser 530 535 540 Tyr Thr Tyr Glu Trp Ser Phe Arg Lys Asp Val AsnMet Ile Leu Gln 545 550 555 560 Ser Thr Leu Gly Asn Asp Leu Arg Val AspGly Ala Ser Val Arg Ile 565 570 575 Asp Ser Val Asn Leu Tyr Ala Asn PhePhe Pro Met Ala His Asn Thr 580 585 590 Ala Ser Thr Leu Glu Ala Met LeuArg Asn Asp Thr Asn Asp Gln Ser 595 600 605 Phe Asn Asp Tyr Leu Ser AlaAla Asn Met Leu Tyr Pro Ile Pro Ala 610 615 620 Asn Ala Thr Asn Val ProIle Ser Ile Pro Ser Arg Asn Trp Ala Ala 625 630 635 640 Phe Arg Gly TrpSer Phe Thr Arg Leu Lys Ala Lys Glu Thr Pro Ser 645 650 655 Leu Gly SerGly Phe Asp Pro Tyr Phe Val Tyr Ser Gly Thr Ile Pro 660 665 670 Tyr LeuAsp Gly Ser Phe Tyr Leu Asn His Thr Phe Lys Arg Leu Ser 675 680 685 IleMet Phe Asp Ser Ser Val Ser Trp Pro Gly Asn Asp Arg Leu Leu 690 695 700Thr Pro Asn Glu Phe Glu Ile Lys Arg Ile Val Asp Gly Glu Gly Tyr 705 710715 720 Asn Val Ala Gln Ser Asn Met Thr Lys Asp Trp Phe Leu Ile Gln Met725 730 735 Leu Ser His Tyr Asn Ile Gly Tyr Gln Gly Phe Tyr Val Pro GluGly 740 745 750 Tyr Lys Asp Arg Met Tyr Ser Phe Phe Arg Asn Phe Gln ProMet Ser 755 760 765 Arg Gln Val Pro Asp Pro Thr Ala Ala Gly Tyr Gln AlaVal Pro Leu 770 775 780 Pro Arg Gln His Asn Asn Ser Gly Phe Val Gly TyrMet Gly Pro Thr 785 790 795 800 Met Arg Glu Gly Gln Pro Tyr Pro Ala AsnTyr Pro Tyr Pro Leu Ile 805 810 815 Gly Ala Thr Ala Val Pro Ala Ile ThrGln Lys Lys Phe Leu Cys Asp 820 825 830 Arg Val Met Trp Arg Ile Pro PheSer Ser Asn Phe Met Ser Met Gly 835 840 845 Ala Leu Thr Asp Leu Gly GlnAsn Met Leu Tyr Ala Asn Ser Ala His 850 855 860 Ala Leu Asp Met Thr PheGlu Val Asp Pro Met Asn Glu Pro Thr Leu 865 870 875 880 Leu Tyr Met LeuPhe Glu Val Phe Asp Val Val Arg Val His Gln Pro 885 890 895 His Arg GlyIle Ile Glu Ala Val Tyr Leu Arg Thr Pro Phe Ser Ala 900 905 910 Gly AsnAla Thr Thr 915 37 533 PRT simian adenovirus SV-39 37 Met Lys Arg AlaLys Val Glu Glu Gly Phe Asn Pro Val Tyr Pro Tyr 1 5 10 15 Gly Tyr SerThr Pro Thr Asp Val Ala Pro Pro Phe Val Ala Ser Asp 20 25 30 Gly Leu GlnGlu Asn Pro Pro Gly Val Leu Ser Leu Lys Ile Ser Lys 35 40 45 Pro Leu ThrPhe Asn Ala Ser Lys Ala Leu Ser Leu Ala Ile Gly Pro 50 55 60 Gly Leu LysIle Gln Asp Gly Lys Leu Val Gly Glu Gly Gln Ala Ile 65 70 75 80 Leu AlaAsn Leu Pro Leu Gln Ile Thr Asn Asn Thr Ile Ser Leu Arg 85 90 95 Phe GlyAsn Thr Leu Ala Leu Asn Asp Asn Asn Glu Leu Gln Thr Thr 100 105 110 LeuLys Ser Ser Ser Pro Leu Lys Ile Thr Asp Gln Thr Leu Ser Leu 115 120 125Asn Ile Gly Asp Ser Leu Ala Ile Lys Asp Asp Lys Leu Glu Ser Ala 130 135140 Leu Gln Ala Thr Leu Pro Leu Ser Ile Ser Asn Asn Thr Ile Ser Leu 145150 155 160 Asn Val Gly Thr Gly Leu Thr Ile Asn Gly Asn Val Leu Gln AlaVal 165 170 175 Pro Leu Asn Ala Leu Ser Pro Leu Thr Ile Ser Asn Asn AsnIle Ser 180 185 190 Leu Arg Tyr Gly Ser Ser Leu Thr Val Leu Asn Asn GluLeu Gln Ser 195 200 205 Asn Leu Thr Val His Ser Pro Leu Lys Leu Asn SerAsn Asn Ser Ile 210 215 220 Ser Leu Asn Thr Leu Ser Pro Phe Arg Ile GluAsn Gly Phe Leu Thr 225 230 235 240 Leu Tyr Leu Gly Thr Lys Ser Gly LeuLeu Val Gln Asn Ser Gly Leu 245 250 255 Lys Val Gln Ala Gly Tyr Gly LeuGln Val Thr Asp Thr Asn Ala Leu 260 265 270 Thr Leu Arg Tyr Leu Ala ProLeu Thr Ile Pro Asp Ser Gly Ser Glu 275 280 285 Gln Gly Ile Leu Lys ValAsn Thr Gly Gln Gly Leu Ser Val Asn Gln 290 295 300 Ala Gly Ala Leu GluThr Ser Leu Gly Gly Gly Leu Lys Tyr Ala Asp 305 310 315 320 Asn Lys IleThr Phe Asp Thr Gly Asn Gly Leu Thr Leu Ser Glu Asn 325 330 335 Lys LeuAla Val Ala Ala Gly Ser Gly Leu Thr Phe Arg Asp Gly Ala 340 345 350 LeuVal Ala Thr Gly Thr Ala Phe Thr Gln Thr Leu Trp Thr Thr Ala 355 360 365Asp Pro Ser Pro Asn Cys Thr Ile Ile Gln Asp Arg Asp Thr Lys Phe 370 375380 Thr Leu Ala Leu Thr Ile Ser Gly Ser Gln Val Leu Gly Thr Val Ser 385390 395 400 Ile Ile Gly Val Lys Gly Pro Leu Ser Ser Ser Ile Pro Ser AlaThr 405 410 415 Val Thr Val Gln Leu Asn Phe Asp Ser Asn Gly Ala Leu LeuSer Ser 420 425 430 Ser Ser Leu Lys Gly Tyr Trp Gly Tyr Arg Gln Gly ProSer Ile Asp 435 440 445 Pro Tyr Pro Ile Ile Asn Ala Leu Asn Phe Met ProAsn Ser Leu Ala 450 455 460 Tyr Pro Pro Gly Gln Glu Ile Gln Ala Lys CysAsn Met Tyr Val Ser 465 470 475 480 Thr Phe Leu Arg Gly Asn Pro Gln ArgPro Ile Val Leu Asn Ile Thr 485 490 495 Phe Asn Asn Gln Thr Ser Gly PheSer Ile Arg Phe Thr Trp Thr Asn 500 505 510 Leu Thr Thr Gly Glu Ala PheAla Met Pro Pro Cys Thr Phe Ser Tyr 515 520 525 Ile Ala Glu Gln Gln 53038 50 DNA Artificial sequence oligomer SV25T 38 aatttaaata cgtagcgcactagtcgcgct aagcgcggat atcatttaaa 50 39 49 DNA Artificial sequenceoligomer SV25B 39 tatttaaatg atatccgcgc ttaagcgcga ctagtgcgct acgtattta49 40 9 PRT Artificial sequence Synthetic peptide which carries theimmunodominant CD8+ T cell epitope for the H-2d haplotype 40 Ala Met GlnMet Leu Lys Glu Thr Ile 1 5 41 19 DNA Artificial sequence 5′ primer forthe rabies virus glycoprotein 41 aagcatttcc gcccaacac 19 42 22 DNAArtificial sequence 3′ primer for rabies virus glycoprotein 42ggttagtgga gcagtaggta ga 22 43 25 DNA Artificial sequence 5′ primer forglutaraldehyde-3-phosphate dehydrogenase (GAPDH) 43 ggtgaaggtcggtgtgaacg gattt 25 44 25 DNA Artificial Sequence 3′ primer for GAPDH 44aatgccaaag ttgtcatgga tgacc 25 45 7228 DNA Artificial Sequence ModifiedHIV-1 gag sequence 45 tggaagggct aatttggtcc caaaaaagac aagagatccttgatctgtgg atctaccaca 60 cacaaggcta cttccctgat tggcagaact acacaccagggccagggatc agatatccac 120 tgacctttgg atggtgcttc aagttagtac cagttgaaccagagcaagta gaagaggcca 180 aataaggaga gaagaacagc ttgttacacc ctatgagccagcatgggatg gaggacccgg 240 agggagaagt attagtgtgg aagtttgaca gcctcctagcatttcgtcac atggcccgag 300 agctgcatcc ggagtactac aaagactgct gacatcgagctttctacaag ggactttccg 360 ctggggactt tccagggagg tgtggcctgg gcgggactggggagtggcga gccctcagat 420 gctacatata agcagctgct ttttgcctgt actgggtctctctggttaga ccagatctga 480 gcctgggagc tctctggcta actagggaac ccactgcttaagcctcaata aagcttgcct 540 tgagtgctca aagtagtgtg tgcccgtctg ttgtgtgactctggtaacta gagatccctc 600 agaccctttt agtcagtgtg gaaaatctct agcagtggcgcccgaacagg gacttgaaag 660 cgaaagtaaa gccagaggag atctctcgac gcaggactcggcttgctgaa gcgcgcgtcg 720 acagagag atg ggt gcg aga gcg tca gta tta agcggg gga gaa tta gat 770 Met Gly Ala Arg Ala Ser Val Leu Ser Gly Gly GluLeu Asp 1 5 10 cga tgg gaa aaa att cgg tta agg cca ggg gga aag aag aagtac aag 818 Arg Trp Glu Lys Ile Arg Leu Arg Pro Gly Gly Lys Lys Lys TyrLys 15 20 25 30 cta aag cac atc gta tgg gca agc agg gag cta gaa cga ttcgca gtt 866 Leu Lys His Ile Val Trp Ala Ser Arg Glu Leu Glu Arg Phe AlaVal 35 40 45 aat cct ggc ctg tta gaa aca tca gaa ggc tgt aga caa ata ctggga 914 Asn Pro Gly Leu Leu Glu Thr Ser Glu Gly Cys Arg Gln Ile Leu Gly50 55 60 cag cta caa cca tcc ctt cag aca gga tca gag gag ctt cga tca cta962 Gln Leu Gln Pro Ser Leu Gln Thr Gly Ser Glu Glu Leu Arg Ser Leu 6570 75 tac aac aca gta gca acc ctc tat tgt gtg cac cag cgg atc gag atc1010 Tyr Asn Thr Val Ala Thr Leu Tyr Cys Val His Gln Arg Ile Glu Ile 8085 90 aag gac acc aag gaa gct tta gac aag ata gag gaa gag caa aac aag1058 Lys Asp Thr Lys Glu Ala Leu Asp Lys Ile Glu Glu Glu Gln Asn Lys 95100 105 110 tcc aag aag aag gcc cag cag gca gca gct gac aca gga cac agcaat 1106 Ser Lys Lys Lys Ala Gln Gln Ala Ala Ala Asp Thr Gly His Ser Asn115 120 125 cag gtc agc caa aat tac cct ata gtg cag aac atc cag ggg caaatg 1154 Gln Val Ser Gln Asn Tyr Pro Ile Val Gln Asn Ile Gln Gly Gln Met130 135 140 gta cat cag gcc ata tca cct aga act tta aat gca tgg gta aaagta 1202 Val His Gln Ala Ile Ser Pro Arg Thr Leu Asn Ala Trp Val Lys Val145 150 155 gta gaa gag aag gct ttc agc cca gaa gtg ata ccc atg ttt tcagca 1250 Val Glu Glu Lys Ala Phe Ser Pro Glu Val Ile Pro Met Phe Ser Ala160 165 170 tta tca gaa gga gcc acc cca cag gac ctg aac acg atg ttg aacacc 1298 Leu Ser Glu Gly Ala Thr Pro Gln Asp Leu Asn Thr Met Leu Asn Thr175 180 185 190 gtg ggg gga cat caa gca gcc atg caa atg tta aaa gag accatc aat 1346 Val Gly Gly His Gln Ala Ala Met Gln Met Leu Lys Glu Thr IleAsn 195 200 205 gag gaa gct gca gaa tgg gat aga gtg cat cca gtg cat gcaggg cct 1394 Glu Glu Ala Ala Glu Trp Asp Arg Val His Pro Val His Ala GlyPro 210 215 220 att gca cca ggc cag atg aga gaa cca agg gga agt gac atagca gga 1442 Ile Ala Pro Gly Gln Met Arg Glu Pro Arg Gly Ser Asp Ile AlaGly 225 230 235 act act agt acc ctt cag gaa caa ata gga tgg atg aca aataat cca 1490 Thr Thr Ser Thr Leu Gln Glu Gln Ile Gly Trp Met Thr Asn AsnPro 240 245 250 cct atc cca gta gga gag atc tac aag agg tgg ata atc ctggga ttg 1538 Pro Ile Pro Val Gly Glu Ile Tyr Lys Arg Trp Ile Ile Leu GlyLeu 255 260 265 270 aac aag atc gtg agg atg tat agc cct acc agc att ctggac ata aga 1586 Asn Lys Ile Val Arg Met Tyr Ser Pro Thr Ser Ile Leu AspIle Arg 275 280 285 caa gga cca aag gaa ccc ttt aga gac tat gta gac cggttc tat aaa 1634 Gln Gly Pro Lys Glu Pro Phe Arg Asp Tyr Val Asp Arg PheTyr Lys 290 295 300 act cta aga gct gag caa gct tca cag gag gta aaa aattgg atg aca 1682 Thr Leu Arg Ala Glu Gln Ala Ser Gln Glu Val Lys Asn TrpMet Thr 305 310 315 gaa acc ttg ttg gtc caa aat gcg aac cca gat tgt aagacc atc ctg 1730 Glu Thr Leu Leu Val Gln Asn Ala Asn Pro Asp Cys Lys ThrIle Leu 320 325 330 aag gct ctc ggc cca gcg gct aca cta gaa gaa atg atgaca gca tgt 1778 Lys Ala Leu Gly Pro Ala Ala Thr Leu Glu Glu Met Met ThrAla Cys 335 340 345 350 cag gga gta gga gga ccc ggc cat aag gca aga gttttg tag 1820 Gln Gly Val Gly Gly Pro Gly His Lys Ala Arg Val Leu 355 360ggatccacta gttctagact cgaggggggg cccggtacct ttaagaccaa tgacttacaa 1880ggcagctgta gatcttagcc actttttaaa agaaaagggg ggactggaag ggctaattca 1940ctcccaaaga agacaagata tccttgatct gtggatctac cacacacaag gctacttccc 2000tgattggcag aactacacac cagggccagg ggtcagatat ccactgacct ttggatggtg 2060ctacaagcta gtaccagttg agccagataa ggtagaagag gccaataaag gagagaacac 2120cagcttgtta caccctgtga gcctgcatgg aatggatgac cctgagagag aagtgttaga 2180gtggaggttt gacagccgcc tagcatttca tcacgtggcc cgagagctgc atccggagta 2240cttcaagaac tgctgacatc gagcttgcta caagggactt tccgctgggg actttccagg 2300gaggcgtggc ctgggcggga ctggggagtg gcgagccctc agatgctgca tataagcagc 2360tgctttttgc ctgtactggg tctctctggt tagaccagat ctgagcctgg gagctctctg 2420gctaactagg gaacccactg cttaagcctc aataaagctt gccttgagtg cttcaagtag 2480tgtgtgcccg tctgttgtgt gactctggta actagagatc cctcagaccc ttttagtcag 2540tgtggaaaat ctctagcacc ccccaggagg tagaggttgc agtgagccaa gatcgcgcca 2600ctgcattcca gcctgggcaa gaaaacaaga ctgtctaaaa taataataat aagttaaggg 2660tattaaatat atttatacat ggaggtcata aaaatatata tatttgggct gggcgcagtg 2720gctcacacct gcgcccggcc ctttgggagg ccgaggcagg tggatcacct gagtttggga 2780gttccagacc agcctgacca acatggagaa accccttctc tgtgtatttt tagtagattt 2840tattttatgt gtattttatt cacaggtatt tctggaaaac tgaaactgtt tttcctctac 2900tctgatacca caagaatcat cagcacagag gaagacttct gtgatcaaat gtggtgggag 2960agggaggttt tcaccagcac atgagcagtc agttctgccg cagactcggc gggtgtcctt 3020cggttcagtt ccaacaccgc ctgcctggag agaggtcaga ccacagggtg agggctcagt 3080ccccaagaca taaacaccca agacataaac acccaacagg tccaccccgc ctgctgccca 3140ggcagagccg attcaccaag acgggaatta ggatagagaa agagtaagtc acacagagcc 3200ggctgtgcgg gagaacggag ttctattatg actcaaatca gtctccccaa gcattcgggg 3260atcagagttt ttaaggataa cttagtgtgt agggggccag tgagttggag atgaaagcgt 3320agggagtcga aggtgtcctt ttgcgccgag tcagttcctg ggtgggggcc acaagatcgg 3380atgagccagt ttatcaatcc gggggtgcca gctgatccat ggagtgcagg gtctgcaaaa 3440tatctcaagc actgattgat cttaggtttt acaatagtga tgttacccca ggaacaattt 3500ggggaaggtc agaatcttgt agcctgtagc tgcatgactc ctaaaccata atttcttttt 3560tgtttttttt tttttatttt tgagacaggg tctcactctg tcacctaggc tggagtgcag 3620tggtgcaatc acagctcact gcagccccta gagcggccgc caccgcggtg gagctccaat 3680tcgccctata gtgagtcgta ttacaattca ctggccgtcg ttttacaacg tcgtgactgg 3740gaaaaccctg gcgttaccca acttaatcgc cttgcagcac atcccccttt cgccagctgg 3800cgtaatagcg aagaggcccg caccgatcgc ccttcccaac agttgcgcag cctgaatggc 3860gaatggcgcg aaattgtaaa cgttaatatt ttgttaaaat tcgcgttaaa tttttgttaa 3920atcagctcat tttttaacca ataggccgaa atcggcaaaa tcccttataa atcaaaagaa 3980tagaccgaga tagggttgag tgttgttcca gtttggaaca agagtccact attaaagaac 4040gtggactcca acgtcaaagg gcgaaaaacc gtctatcagg gcgatggccc actacgtgaa 4100ccatcaccct aatcaagttt tttggggtcg aggtgccgta aagcactaaa tcggaaccct 4160aaagggagcc cccgatttag agcttgacgg ggaaagccgg cgaacgtggc gagaaaggaa 4220gggaagaaag cgaaaggagc gggcgctagg gcgctggcaa gtgtagcggt cacgctgcgc 4280gtaaccacca cacccgccgc gcttaatgcg ccgctacagg gcgcgtccca ggtggcactt 4340ttcggggaaa tgtgcgcgga acccctattt gtttattttt ctaaatacat tcaaatatgt 4400atccgctcat gagacaataa ccctgataaa tgcttcaata atattgaaaa aggaagagta 4460tgagtattca acatttccgt gtcgccctta ttcccttttt tgcggcattt tgccttcctg 4520tttttgctca cccagaaacg ctggtgaaag taaaagatgc tgaagatcag ttgggtgcac 4580gagtgggtta catcgaactg gatctcaaca gcggtaagat ccttgagagt tttcgccccg 4640aagaacgttt tccaatgatg agcactttta aagttctgct atgtggcgcg gtattatccc 4700gtattgacgc cgggcaagag caactcggtc gccgcataca ctattctcag aatgacttgg 4760ttgagtactc accagtcaca gaaaagcatc ttacggatgg catgacagta agagaattat 4820gcagtgctgc cataaccatg agtgataaca ctgcggccaa cttacttctg acaacgatcg 4880gaggaccgaa ggagctaacc gcttttttgc acaacatggg ggatcatgta actcgccttg 4940atcgttggga accggagctg aatgaagcca taccaaacga cgagcgtgac accacgatgc 5000ctgtagcaat ggcaacaacg ttgcgcaaac tattaactgg cgaactactt actctagctt 5060cccggcaaca attaatagac tggatggagg cggataaagt tgcaggacca cttctgcgct 5120cggcccttcc ggctggctgg tttattgctg ataaatctgg agccggtgag cgtgggtctc 5180gcggtatcat tgcagcactg gggccagatg gtaagccctc ccgtatcgta gttatctaca 5240cgacggggag tcaggcaact atggatgaac gaaatagaca gatcgctgag ataggtgcct 5300cactgattaa gcattggtaa ctgtcagacc aagtttactc atatatactt tagattgatt 5360taaaacttca tttttaattt aaaaggatct aggtgaagat cctttttgat aatctcatga 5420ccaaaatccc ttaacgtgag ttttcgttcc actgagcgtc agaccccgta gaaaagatca 5480aaggatcttc ttgagatcct ttttttctgc gcgtaatctg ctgcttgcaa acaaaaaaac 5540caccgctacc agcggtggtt tgtttgccgg atcaagagct accaactctt tttccgaagg 5600taactggctt cagcagagcg cagataccaa atactgtcct tctagtgtag ccgtagttag 5660gccaccactt caagaactct gtagcaccgc ctacatacct cgctctgcta atcctgttac 5720cagtggctgc tgccagtggc gataagtcgt gtcttaccgg gttggactca agacgatagt 5780taccggataa ggcgcagcgg tcgggctgaa cggggggttc gtgcacacag cccagcttgg 5840agcgaacgac ctacaccgaa ctgagatacc tacagcgtga gctatgagaa agcgccacgc 5900ttcccgaagg gagaaaggcg gacaggtatc cggtaagcgg cagggtcgga acaggagagc 5960gcacgaggga gcttccaggg ggaaacgcct ggtatcttta tagtcctgtc gggtttcgcc 6020acctctgact tgagcgtcga tttttgtgat gctcgtcagg ggggcggagc ctatggaaaa 6080acgccagcaa cgcggccttt ttacggttcc tggccttttg ctggcctttt gctcacatgt 6140tctttcctgc gttatcccct gattctgtgg ataaccgtat taccgccttt gagtgagctg 6200ataccgctcg ccgcagccga acgaccgagc gcagcgagtc agtgagcgag gaagcggaag 6260agcgcccaat acgcaaaccg cctctccccg cgcgttggcc gattcattaa tgcagctggc 6320acgacaggtt tcccgactgg aaagcgggca gtgagcgcaa cgcaattaat gtgagttagc 6380tcactcatta ggcaccccag gctttacact ttatgcttcc ggctcgtatg ttgtgtggaa 6440ttgtgagcgg ataacaattt cacacaggaa acagctatga ccatgattac gccaagctcg 6500gaattaaccc tcactaaagg gaacaaaagc tgctgcaggg tccctaactg ccaagcccca 6560cagtgtgccc tgaggctgcc ccttccttct agcggctgcc cccactcggc tttgctttcc 6620ctagtttcag ttacttgcgt tcagccaagg tctgaaacta ggtgcgcaca gagcggtaag 6680actgcgagag aaagagacca gctttacagg gggtttatca cagtgcaccc tgacagtcgt 6740cagcctcaca gggggtttat cacattgcac cctgacagtc gtcagcctca cagggggttt 6800atcacagtgc acccttacaa tcattccatt tgattcacaa tttttttagt ctctactgtg 6860cctaacttgt aagttaaatt tgatcagagg tgtgttccca gaggggaaaa cagtatatac 6920agggttcagt actatcgcat ttcaggcctc cacctgggtc ttggaatgtg tcccccgagg 6980ggtgatgact acctcagttg gatctccaca ggtcacagtg acacaagata accaagacac 7040ctcccaaggc taccacaatg ggccgccctc cacgtgcaca tggccggagg aactgccatg 7100tcggaggtgc aagcacacct gcgcatcaga gtccttggtg tggagggagg gaccagcgca 7160gcttccagcc atccacctga tgaacagaac ctagggaaag ccccagttct acttacacca 7220ggaaaggc 7228 46 363 PRT Artificial Sequence Synthetic Construct 46 MetGly Ala Arg Ala Ser Val Leu Ser Gly Gly Glu Leu Asp Arg Trp 1 5 10 15Glu Lys Ile Arg Leu Arg Pro Gly Gly Lys Lys Lys Tyr Lys Leu Lys 20 25 30His Ile Val Trp Ala Ser Arg Glu Leu Glu Arg Phe Ala Val Asn Pro 35 40 45Gly Leu Leu Glu Thr Ser Glu Gly Cys Arg Gln Ile Leu Gly Gln Leu 50 55 60Gln Pro Ser Leu Gln Thr Gly Ser Glu Glu Leu Arg Ser Leu Tyr Asn 65 70 7580 Thr Val Ala Thr Leu Tyr Cys Val His Gln Arg Ile Glu Ile Lys Asp 85 9095 Thr Lys Glu Ala Leu Asp Lys Ile Glu Glu Glu Gln Asn Lys Ser Lys 100105 110 Lys Lys Ala Gln Gln Ala Ala Ala Asp Thr Gly His Ser Asn Gln Val115 120 125 Ser Gln Asn Tyr Pro Ile Val Gln Asn Ile Gln Gly Gln Met ValHis 130 135 140 Gln Ala Ile Ser Pro Arg Thr Leu Asn Ala Trp Val Lys ValVal Glu 145 150 155 160 Glu Lys Ala Phe Ser Pro Glu Val Ile Pro Met PheSer Ala Leu Ser 165 170 175 Glu Gly Ala Thr Pro Gln Asp Leu Asn Thr MetLeu Asn Thr Val Gly 180 185 190 Gly His Gln Ala Ala Met Gln Met Leu LysGlu Thr Ile Asn Glu Glu 195 200 205 Ala Ala Glu Trp Asp Arg Val His ProVal His Ala Gly Pro Ile Ala 210 215 220 Pro Gly Gln Met Arg Glu Pro ArgGly Ser Asp Ile Ala Gly Thr Thr 225 230 235 240 Ser Thr Leu Gln Glu GlnIle Gly Trp Met Thr Asn Asn Pro Pro Ile 245 250 255 Pro Val Gly Glu IleTyr Lys Arg Trp Ile Ile Leu Gly Leu Asn Lys 260 265 270 Ile Val Arg MetTyr Ser Pro Thr Ser Ile Leu Asp Ile Arg Gln Gly 275 280 285 Pro Lys GluPro Phe Arg Asp Tyr Val Asp Arg Phe Tyr Lys Thr Leu 290 295 300 Arg AlaGlu Gln Ala Ser Gln Glu Val Lys Asn Trp Met Thr Glu Thr 305 310 315 320Leu Leu Val Gln Asn Ala Asn Pro Asp Cys Lys Thr Ile Leu Lys Ala 325 330335 Leu Gly Pro Ala Ala Thr Leu Glu Glu Met Met Thr Ala Cys Gln Gly 340345 350 Val Gly Gly Pro Gly His Lys Ala Arg Val Leu 355 360 47 311 PRTChimpanzee type adenovirus 47 Asn Thr Cys Gln Trp Thr Tyr Lys Ala AspGly Glu Thr Ala Thr Glu 1 5 10 15 Lys Thr Tyr Thr Tyr Gly Asn Ala ProVal Gln Gly Ile Asn Ile Thr 20 25 30 Lys Asp Gly Ile Gln Leu Gly Thr AspThr Asp Asp Gln Pro Ile Tyr 35 40 45 Ala Asp Lys Thr Tyr Gln Pro Glu ProGln Val Gly Asp Ala Glu Trp 50 55 60 His Asp Ile Thr Gly Thr Asp Glu LysTyr Gly Gly Arg Ala Leu Lys 65 70 75 80 Pro Asp Thr Lys Met Lys Pro CysTyr Gly Ser Phe Ala Lys Pro Thr 85 90 95 Asn Lys Glu Gly Gly Gln Ala AsnVal Lys Thr Gly Thr Gly Thr Thr 100 105 110 Lys Glu Tyr Asp Ile Asp MetAla Phe Phe Asp Asn Arg Ser Ala Ala 115 120 125 Ala Ala Gly Leu Ala ProGlu Ile Val Leu Tyr Thr Glu Asn Val Asp 130 135 140 Leu Glu Thr Pro AspThr His Ile Val Tyr Lys Ala Gly Thr Asp Asp 145 150 155 160 Ser Ser SerSer Ile Asn Leu Gly Gln Gln Ala Met Pro Asn Arg Pro 165 170 175 Val TyrIle Gly Phe Arg Asp Asn Phe Ile Gly Leu Met Tyr Tyr Asn 180 185 190 SerThr Gly Asn Met Gly Val Leu Ala Gly Gln Ala Ser Gln Leu Asn 195 200 205Ala Val Val Asp Leu Gln Asp Arg Asn Thr Glu Leu Ser Tyr Gln Leu 210 215220 Leu Leu Asp Ser Leu Gly Asp Arg Thr Arg Tyr Phe Ser Met Trp Asn 225230 235 240 Gln Ala Val Asp Ser Tyr Asp Pro Asp Val Arg Ile Ile Glu AsnHis 245 250 255 Gly Val Glu Asp Glu Leu Pro Asn Tyr Cys Phe Pro Leu AspAla Val 260 265 270 Gly Arg Thr Asp Thr Tyr Gln Gly Ile Lys Ala Asn GlyThr Asp Gln 275 280 285 Thr Thr Trp Thr Lys Asp Asp Ser Val Asn Asp AlaAsn Glu Ile Gly 290 295 300 Lys Gly Asn Pro Phe Ala Met 305 310 48 314PRT Human adenovirus type 4 48 Asn Thr Cys Gln Trp Lys Asp Ser Asp SerLys Met His Thr Phe Gly 1 5 10 15 Ala Ala Ala Met Pro Gly Val Thr GlyLys Lys Ile Glu Ala Asp Gly 20 25 30 Leu Pro Ile Arg Ile Asp Ser Thr SerGly Thr Asp Thr Val Ile Tyr 35 40 45 Ala Asp Lys Thr Phe Gln Pro Glu ProGln Val Gly Asn Asp Ser Trp 50 55 60 Val Asp Thr Asn Gly Ala Glu Glu LysTyr Gly Gly Arg Ala Leu Lys 65 70 75 80 Asp Thr Thr Lys Met Asn Pro CysTyr Gly Ser Phe Ala Lys Pro Thr 85 90 95 Asn Lys Glu Gly Gly Gln Ala AsnLeu Lys Asp Ser Glu Pro Ala Ala 100 105 110 Thr Thr Pro Asn Tyr Asp IleAsp Leu Ala Phe Phe Asp Ser Lys Thr 115 120 125 Ile Val Ala Asn Tyr AspPro Asp Ile Val Met Tyr Thr Glu Asn Val 130 135 140 Asp Leu Gln Thr ProAsp Thr His Ile Val Tyr Lys Pro Gly Thr Glu 145 150 155 160 Asp Thr SerSer Glu Ser Asn Leu Gly Gln Gln Ala Met Pro Asn Arg 165 170 175 Pro AsnTyr Ile Gly Phe Arg Asp Asn Phe Ile Gly Leu Met Tyr Tyr 180 185 190 AsnSer Thr Gly Asn Met Gly Val Leu Ala Gly Gln Ala Ser Gln Leu 195 200 205Asn Ala Val Val Asp Leu Gln Asp Arg Asn Thr Glu Leu Ser Tyr Gln 210 215220 Leu Leu Leu Asp Ser Leu Gly Asp Arg Thr Arg Tyr Phe Ser Met Trp 225230 235 240 Asn Gln Ala Val Asp Ser Tyr Asp Pro Asp Val Arg Ile Ile GluAsn 245 250 255 His Gly Val Glu Asp Glu Leu Pro Asn Tyr Cys Phe Pro LeuAsn Gly 260 265 270 Val Gly Leu Thr Asp Thr Tyr Gln Gly Val Lys Val LysThr Asp Ala 275 280 285 Gly Ser Glu Lys Trp Asp Lys Asp Asp Thr Thr ValSer Asn Ala Asn 290 295 300 Glu Ile His Val Gly Asn Pro Phe Ala Met 305310 49 318 PRT Human adenovirus type 16 49 Asn Thr Cys Gln Trp Lys AspSer Asp Ser Lys Met His Thr Phe Gly 1 5 10 15 Val Ala Ala Met Pro GlyVal Thr Gly Lys Lys Ile Glu Ala Asp Gly 20 25 30 Leu Pro Ile Gly Ile AspSer Thr Ser Gly Thr Asp Thr Val Ile Tyr 35 40 45 Ala Asp Lys Thr Phe GlnPro Glu Pro Gln Val Gly Asn Ala Ser Trp 50 55 60 Val Asp Ala Asn Gly ThrGlu Glu Lys Tyr Gly Gly Arg Ala Leu Lys 65 70 75 80 Asp Thr Thr Lys MetLys Pro Cys Tyr Gly Ser Phe Ala Lys Pro Thr 85 90 95 Asn Lys Glu Gly GlyGln Ala Asn Leu Lys Asp Ser Glu Thr Ala Ala 100 105 110 Thr Thr Pro AsnTyr Asp Ile Asp Leu Ala Phe Phe Asp Asn Lys Asn 115 120 125 Ile Ala AlaAsn Tyr Asp Pro Asp Ile Val Met Tyr Thr Glu Asn Val 130 135 140 Asp LeuGln Thr Pro Asp Thr His Ile Val Tyr Lys Pro Gly Thr Glu 145 150 155 160Asp Thr Ser Ser Glu Ser Asn Leu Gly Gln Gln Ala Met Pro Asn Arg 165 170175 Pro Asn Tyr Ile Gly Phe Arg Asp Asn Phe Ile Gly Leu Met Tyr Tyr 180185 190 Asn Ser Thr Gly Asn Met Gly Val Leu Ala Gly Gln Ala Ser Gln Leu195 200 205 Asn Ala Val Val Asp Leu Gln Asp Arg Asn Thr Glu Leu Ser TyrGln 210 215 220 Leu Leu Leu Asp Ser Leu Gly Asp Arg Thr Arg Tyr Phe SerMet Trp 225 230 235 240 Asn Gln Ala Val Asp Ser Tyr Asp Pro Asp Val ArgIle Ile Glu Asn 245 250 255 His Gly Val Glu Asp Glu Leu Pro Asn Tyr CysPhe Pro Leu Asn Gly 260 265 270 Val Gly Phe Thr Asp Thr Tyr Gln Gly ValLys Val Lys Thr Asp Ala 275 280 285 Val Ala Gly Thr Ser Gly Thr Gln TrpAsp Lys Asp Asp Thr Thr Val 290 295 300 Ser Thr Ala Asn Glu Ile His GlyGly Asn Pro Phe Ala Met 305 310 315 50 323 PRT Human adenovirus type 350 Asn Thr Ser Gln Trp Ile Val Thr Thr Asn Gly Asp Asn Ala Val Thr 1 510 15 Thr Thr Thr Asn Thr Phe Gly Ile Ala Ser Met Lys Gly Gly Asn Ile 2025 30 Thr Lys Glu Gly Leu Gln Ile Gly Lys Asp Ile Thr Thr Thr Glu Gly 3540 45 Glu Glu Lys Pro Ile Tyr Ala Asp Lys Thr Tyr Gln Pro Glu Pro Gln 5055 60 Val Gly Glu Glu Ser Trp Thr Asp Thr Asp Gly Thr Asn Glu Lys Phe 6570 75 80 Gly Gly Arg Ala Leu Lys Pro Ala Thr Asn Met Lys Pro Cys Tyr Gly85 90 95 Ser Phe Ala Arg Pro Thr Asn Ile Lys Gly Gly Gln Ala Lys Asn Arg100 105 110 Lys Val Lys Pro Thr Thr Glu Gly Gly Val Glu Thr Glu Glu ProAsp 115 120 125 Ile Asp Met Glu Phe Phe Asp Gly Arg Asp Ala Val Ala GlyAla Leu 130 135 140 Ala Pro Glu Ile Val Leu Tyr Thr Glu Asn Val Asn LeuGlu Thr Pro 145 150 155 160 Asp Ser His Val Val Tyr Lys Pro Glu Thr SerAsn Asn Ser His Ala 165 170 175 Asn Leu Gly Gln Gln Ala Met Pro Asn ArgPro Asn Tyr Ile Gly Phe 180 185 190 Arg Asp Asn Phe Val Gly Leu Met TyrTyr Asn Ser Thr Gly Asn Met 195 200 205 Gly Val Leu Ala Gly Gln Ala SerGln Leu Asn Ala Val Val Asp Leu 210 215 220 Gln Asp Arg Asn Thr Glu LeuSer Tyr Gln Leu Leu Leu Asp Ser Leu 225 230 235 240 Gly Asp Arg Thr ArgTyr Phe Ser Met Trp Asn Gln Ala Val Asp Ser 245 250 255 Tyr Asp Pro AspVal Arg Ile Ile Glu Asn His Gly Ile Glu Asp Glu 260 265 270 Leu Pro AsnTyr Cys Phe Pro Leu Asn Gly Ile Gly Pro Gly His Thr 275 280 285 Tyr GlnGly Ile Lys Lys Val Lys Thr Asp Asp Thr Asn Gly Trp Glu 290 295 300 LysAsp Ala Asn Val Ala Pro Ala Asn Glu Ile Thr Ile Gly Asn Asn 305 310 315320 Leu Ala Met 51 315 PRT Human adenovirus type 7 51 Asn Thr Ser GlnTrp Ile Val Thr Ala Gly Glu Glu Arg Ala Val Thr 1 5 10 15 Thr Thr ThrAsn Thr Phe Gly Ile Ala Ser Met Lys Gly Asp Asn Ile 20 25 30 Thr Lys GluGly Leu Glu Ile Gly Lys Asp Ile Thr Ala Asp Asn Lys 35 40 45 Pro Ile TyrAla Asp Lys Thr Tyr Gln Pro Glu Pro Gln Val Gly Glu 50 55 60 Glu Ser TrpThr Asp Thr Asp Gly Thr Asn Glu Lys Phe Gly Gly Arg 65 70 75 80 Ala LeuLys Pro Ala Thr Lys Met Lys Pro Cys Tyr Gly Ser Phe Ala 85 90 95 Arg ProThr Asn Ile Lys Gly Gly Gln Ala Lys Asn Arg Lys Val Lys 100 105 110 ProThr Glu Gly Asp Val Glu Thr Glu Glu Pro Asp Ile Asp Met Glu 115 120 125Phe Phe Asp Gly Arg Glu Ala Ala Asp Ala Phe Ser Pro Glu Ile Val 130 135140 Leu Tyr Thr Glu Asn Val Asn Leu Glu Thr Pro Asp Ser His Val Val 145150 155 160 Tyr Lys Pro Gly Thr Ser Asp Asp Asn Ser His Ala Asn Leu GlyGln 165 170 175 Gln Ala Met Pro Asn Arg Pro Asn Tyr Ile Gly Phe Arg AspAsn Phe 180 185 190 Val Gly Leu Met Tyr Tyr Asn Ser Thr Gly Asn Met GlyVal Leu Ala 195 200 205 Gly Gln Ala Ser Gln Leu Asn Ala Val Val Asp LeuGln Asp Arg Asn 210 215 220 Thr Glu Leu Ser Tyr Gln Leu Leu Leu Asp SerLeu Gly Asp Arg Thr 225 230 235 240 Arg Tyr Phe Ser Met Trp Asn Gln AlaVal Asp Ser Tyr Asp Pro Asp 245 250 255 Val Arg Ile Ile Glu Asn His GlyIle Glu Asp Glu Leu Pro Asn Tyr 260 265 270 Cys Phe Pro Leu Asp Gly IleGly Pro Ala Lys Thr Tyr Gln Gly Ile 275 280 285 Lys Ser Lys Asp Asn GlyTrp Glu Lys Asp Asp Asn Val Ser Lys Ser 290 295 300 Asn Glu Ile Ala IleGly Asn Asn Gln Ala Met 305 310 315 52 345 PRT Human adenovirus type 252 Asn Ser Cys Glu Trp Glu Gln Thr Glu Asp Ser Gly Arg Ala Val Ala 1 510 15 Glu Asp Glu Glu Glu Glu Asp Glu Asp Glu Glu Glu Glu Glu Glu Glu 2025 30 Gln Asn Ala Arg Asp Gln Ala Thr Lys Lys Thr His Val Tyr Ala Gln 3540 45 Ala Pro Leu Ser Gly Glu Thr Leu Thr Lys Ser Gly Leu Gln Ile Gly 5055 60 Ser Lys Asn Ala Glu Thr Gln Ala Lys Pro Val Tyr Ala Asp Pro Ser 6570 75 80 Tyr Gln Pro Glu Pro Gln Ile Gly Glu Ser Gln Trp Asn Glu Ala Asp85 90 95 Ala Asn Ala Ala Gly Gly Arg Val Leu Lys Lys Thr Thr Pro Met Lys100 105 110 Pro Tyr Gly Ser Tyr Ala Arg Pro Thr Asn Pro Phe Gly Gly GlnSer 115 120 125 Val Leu Val Pro Asp Glu Lys Gly Val Pro Leu Pro Lys ValAsp Leu 130 135 140 Gln Phe Phe Ser Asn Thr Thr Ser Leu Asn Asp Arg GlnGly Asn Ala 145 150 155 160 Thr Lys Pro Lys Val Val Leu Tyr Ser Glu AspVal Asn Met Glu Thr 165 170 175 Pro Asp Thr His Leu Ser Tyr Lys Pro GlyLys Gly Asp Glu Asn Ser 180 185 190 Lys Ala Met Leu Gly Gln Gln Ser MetPro Asn Arg Pro Asn Tyr Ile 195 200 205 Ala Phe Arg Asp Asn Phe Ile GlyLeu Met Tyr Tyr Asn Ser Thr Gly 210 215 220 Asn Met Gly Val Leu Ala GlyGln Ala Ser Gln Leu Asn Ala Val Val 225 230 235 240 Asp Leu Gln Asp ArgAsn Thr Glu Leu Ser Tyr Gln Leu Leu Leu Asp 245 250 255 Ser Ile Gly AspArg Thr Arg Tyr Phe Ser Met Trp Asn Gln Ala Val 260 265 270 Asp Ser TyrAsp Pro Asp Val Arg Ile Ile Glu Asn His Gly Thr Glu 275 280 285 Asp GluLeu Pro Asn Tyr Cys Phe Pro Leu Gly Gly Ile Gly Val Thr 290 295 300 AspThr Tyr Gln Ala Ile Lys Ala Asn Gly Asn Gly Ser Gly Asp Asn 305 310 315320 Gly Asp Thr Thr Trp Thr Lys Asp Glu Thr Phe Ala Thr Arg Asn Glu 325330 335 Ile Gly Val Gly Asn Asn Phe Ala Met 340 345

What is claimed is:
 1. A replication defective simian adenoviral vectorcontaining, in a simian adenoviral capsid, simian adenoviralcis-elements and a heterologous gene operably linked to expressioncontrol sequences, wherein the simian adenoviral capsid is derived froma chimpanzee adenovirus selected from the group consisting of Pan 5, Pan6, and Pan
 7. 2. The simian adenoviral vector according to claim 1 thatis replication defective due to the absence of the ability to expressadenoviral E1a and E1b.
 3. The simian adenoviral vector according toclaim 1 wherein the delayed early gene E3 is eliminated.
 4. The simianadenoviral vector according to claim 1 having a functional deletion inthe E4 gene.
 5. The simian adenoviral vector according to claim 1 whichcontains a deletion in the delayed early gene E2a.
 6. The simianadenoviral vector according to claim 1 having a deletion in any of thelate genes L1 to L5 of the simian adenoviral genome.
 7. The simianadenoviral vector according to claim 1 wherein the heterologous gene isdirected to the prevention and treatment of disease caused by a virusselected from the group consisting of Human immunodeficiency virus,Simian immunodeficiency virus, Respiratory syncytial virus,Parainfluenza virus types 1-3, Influenza virus, Herpes simplex virus,Human cytomegalovirus, hepatitis viruses, Human papillomavirus,poliovirus, rotavirus, caliciviruses, Measles virus, Mumps virus,Rubella virus, adenovirus, rabies virus, canine distemper virus,rinderpest virus, coronavirus, parvovirus, infectious rhinotracheitisviruses, feline leukemia virus, feline infectious peritonitis virus,avian infectious bursal disease virus, Newcastle disease virus, Marek'sdisease virus, porcine respiratory and reproductive syndrome virus,equine arteritis virus and Encephalitis viruses.
 8. The simianadenoviral vector according to claim 1 wherein the heterologous gene isdirected to the prevention and treatment of disease caused by abacterium selected from the group consisting of Haemophilus influenzae,Haemophilus somnus, Moraxella catarrhalis, Streptococcus pneumoniae,Streptococcus pyogenes, Streptococcus agalactiae, Streptococcusfaecalis, Helicobacter pylori, Neisseria meningitidis, Neisseriagonorrhoeae, Chlamydia trachomatis, Chlamydia pneumoniae, Chlamydiapsittaci, Bordetella pertussis, Salmonella typhi, Salmonellatyphimurium, Salmonella choleraesuis, Escherichia coli, Shigella, Vibriocholerae, Corynebacterium diphtheriae, Mycobacterium tuberculosis,Mycobacterium avium, Mycobacterium intracellulare complex, Proteusmirabilis, Proteus vulgaris, Staphylococcus aureus, Clostridium tetani,Leptospira interrogans, Borrelia burgdorferi, Pasteurella haemolytica,Pasteurella multocida, Actinobacillus pleuropneumoniae and Mycoplasmagallisepticum.
 9. The simian adenoviral vector according to claim 1wherein the heterologous gene is directed to the prevention andtreatment of disease caused by a fungus selected from the groupconsisting of Aspergillis, Blastomyces, Candida, Coccidiodes,Cryptococcus and Histoplasma.
 10. The simian adenoviral vector accordingto claim 1 wherein the heterologous gene is directed to the preventionand treatment of disease caused by a parasite selected from the groupconsisting of Leishmania major, Ascaris, Trichuris, Giardia,Schistosoma, Cryptosporidium, Trichomonas, Toxoplasma gondii andPneumocystis cariniii.
 11. The simian adenoviral vector according toclaim 1 wherein the heterologous gene is directed to eliciting ananti-cancer effect utilizing a cancer antigen or tumor-associatedantigen selected from the group consisting of prostate specific antigen,carcino-embryonic antigen, MUC-1, Her2, CA-125 and MAGE-3.
 12. A methodof producing a simian adenoviral vector according to claim
 11. 13. Areplication defective simian adenoviral vector containing, in a simianadenoviral capsid, simian adenoviral cis-elements and a heterologousgene operably linked to expression control sequences, wherein the simianadenoviral capsid is derived from an adenovirus selected from the groupconsisting of baboon adenovirus ATCC-VR 275, Rhesus monkey strains,ATCC-VR 209, ATCC-VR 275, ATCC VR 353, ATCC VR 355, and African GreenMonkey strains ATCC VR-541, ATCC VR 941, ATCC VR 942, and ATCC
 943. 14.The simian adenoviral vector according to claim 13 that is replicationdefective due to the absence of the ability to express adenoviral E1aand E1b.
 15. The simian adenoviral vector according to claim 13 whereinthe delayed early gene E3 is eliminated.
 16. The simian adenoviralvector according to claim 13 having a functional deletion in the E4gene.
 17. The simian adenoviral vector according to claim 13 whichcontains a deletion in the delayed early gene E2a.
 18. The simianadenoviral vector according to claim 13 having a deletion in any of thelate genes L1 to L5 of the simian adenoviral genome.
 19. The simianadenoviral vector according to claim 13 wherein the heterologous gene isdirected to the prevention and treatment of disease caused by a virusselected from the group consisting of Human immunodeficiency virus,Simian immunodeficiency virus, Respiratory syncytial virus,Parainfluenza virus types 1-3, Influenza virus, Herpes simplex virus,Human cytomegalovirus, hepatitis viruses, Human papillomavirus,poliovirus, rotavirus, caliciviruses, Measles virus, Mumps virus,Rubella virus, adenovirus, rabies virus, canine distemper virus,rinderpest virus, coronavirus, parvovirus, infectious rhinotracheitisviruses, feline leukemia virus, feline infectious peritonitis virus,avian infectious bursal disease virus, Newcastle disease virus, Marek'sdisease virus, porcine respiratory and reproductive syndrome virus,equine arteritis virus and Encephalitis viruses.
 20. The simianadenoviral vector according to claim 13 wherein the heterologous gene isdirected to the prevention and treatment of disease caused by abacterium selected from the group consisting of Haemophilus influenzae,Haemophilus somnus, Moraxella catarrhalis, Streptococcus pneumoniae,Streptococcus pyogenes, Streptococcus agalactiae, Streptococcusfaecalis, Helicobacter pylori, Neisseria meningitidis, Neisseriagonorrhoeae, Chlamydia trachomatis, Chlamydia pneumoniae, Chlamydiapsittaci, Bordetella pertussis, Salmonella typhi, Salmonellatyphimurium, Salmonella choleraesuis, Escherichia coli, Shigella, Vibriocholerae, Corynebacterium diphtheriae, Mycobacterium tuberculosis,Mycobacterium avium, Mycobacterium intracellulare complex, Proteusmirabilis, Proteus vulgaris, Staphylococcus aureus, Clostridium tetani,Leptospira interrogans, Borrelia burgdorferi, Pasteurella haemolytica,Pasteurella multocida, Actinobacillus pleuropneumoniae and Mycoplasmagallisepticum.
 21. The simian adenoviral vector according to claim 13wherein the heterologous gene is directed to the prevention andtreatment of disease caused by a fungus selected from the groupconsisting of Aspergillis, Blastomyces, Candida, Coccidiodes,Cryptococcus and Histoplasma.
 22. The simian adenoviral vector accordingto claim 13 wherein the heterologous gene is directed to the preventionand treatment of disease caused by a parasite selected from the groupconsisting of Leishmania major, Ascaris, Trichuris, Giardia,Schistosoma, Cryptosporidium, Trichomonas, Toxoplasma gondii andPneumocystis carinii.
 23. The simian adenoviral vector according toclaim 13 wherein the heterologous gene is directed to eliciting ananti-cancer effect utilizing a cancer antigen or tumor-associatedantigen selected from the group consisting of prostate specific antigen,carcino-embryonic antigen, MUC-1, Her2, CA-135 and MAGE-3.
 24. A methodof producing a simian adenoviral vector according to claim 13.